Pyrimidine-2,4-diamine derivatives for treatment of cancer

ABSTRACT

A compound of formula (I), or a pharmaceutically-acceptable salt thereof. The compound is useful in the treatment of cancer or other diseases that may benefit from inhibition of MTH1.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Stage Application under 35 U.S.C. §371 of International Application No. PCT/SE2013/051387, filed on Nov. 26, 2013, which claims the benefit of U.S. Provisional Application No. 61/797,022, filed on Nov. 27, 2012, and Swedish Application No. 1251332-1, filed on Nov. 27, 2012, the entire disclosures of which are hereby incorporated by reference for any and all purposes.

FIELD OF THE INVENTION

The invention relates to novel compounds, compositions and methods for treatment of cancer. In particular, the invention relates to novel compounds, compositions and methods for the treatment of cancers through inhibition of MTH1.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

BACKGROUND

Dysfunctional redox regulation of cellular signalling and an increased ROS (Reactive oxygen species) tension have been demonstrated to play a crucial role in cancer etiology, progression and metastasis (Zhang et al., Antioxid Redox Signal 15(11)2011:2876-2908). ROS mediates tumor-promoting characteristics, such as e.g. unrestrained proliferation, survival signaling, increased migration, angiogenesis. ROS are generated during cell metabolism and are highly reactive with macromolecules such as DNA, proteins and lipids. Exposure of nucleic acids to ROS can create more than 20 oxidatively modified nucleotides, of which 8-oxo-7,8-dihydroxyguanine (8-oxo-dG) is most abundant. 8-oxo-dG plays a pivotal role in mutagenesis (Sekiguchi and Tsuzuki., Oncogene 21(58)2002:8895-906). To protect themselves from carcinogenic effects, mammalian cells are armed with a set of repair enzymes to remove the oxidized nucleotides to maintain genome integrity. One of these protective enzymes is MTH1 (MutT homologue 1, 8-oxo-dGTPase, NUDT1). Interestingly, MTH1 is upregulated in various cancer forms, suggesting that the cancer cell rely on MTH1 function to survive the increased DNA lesion (Human Proteinatlas, Koketsu et al., Hepatogastroenterology, 51(57)2004:638-41). Suppression of MTH1 level and activity by using RNAi technology, leads to reduced cancer cell survival, premature senescence and DNA strand breaks (Rai et al, PNAS, 106(1)2009:169-174), Helleday et al unpublished data). Interestingly, lung cancers which spontaneously form in OGG−/− mice are prevented from forming in crosses with the MTH1−/− mice, suggesting that MTH1 is required for lung cancer cells to survive (Sakumi et al., Cancer Res 63, 2003: 902). We have observed that downregulation of MTH1 protein levels in human colon cancer tumors in xenograft mice model reduced tumor growth and significantly shrinked the tumour (Helleday et al, unpublished data).

In tumour cells, reducing the capacity to eliminate oxidised dNTPs by inhibiting MTH1 activity, will reduce cancer cell survival and hence be a promising novel anticancer therapy, either as monotherapy in cancer forms with high oxidative stress levels and/or in combination with radiotherapy and chemotherapy drugs.

Shortcomings and Complications with Current Treatment

Today's treatment of cancer is not effective for all patients with diagnosed disease also including a large proportion of patients that experience adverse effects from treatments with existing therapies or where resistance to on-going therapy is developed over time.

PRIOR ART

Engelhardt, H. et al. Journal of Medicinal Chemistry (2013), 56(11), 4264-4276 and US patent application US 2010/0016344 disclose certain 6-aryl-2,4-diaminopyrimidines having an additional pyrimidine appendage as histamine H4 receptor modulators. The compounds are claimed to be useful for a various diseases including cancer pain, but their use in the treatment of cancer as such is neither disclosed or suggested.

International patent application WO 2013/066839 discloses 6-(3-pyridyl)-(2,4-diaminopyrimidines as HDAC inhibitors. However, the substituent on the 4-amino group contains a prerequisite 5-trifluoromethyl-1,2,4-oxadiazol-3-yl group.

2,4-Diaminopyrimidines substituted in the 6-position with 3-aminoindazoles have been described in international patent application WO 2010/059658. Although also indazoles without the amino groups are mentioned, it is evident from the examples that the 3-amino substituent on the indazole is required for activity. The same document also describes 2,4-diaminopyrimidines substituted in the 6-position by a 3-cyano-2-fluorophenyl group. However, these compounds are merely precursors to the 3-aminoindazoles mentioned above and there is no disclosure or suggestions in the document that they possess any anti-cancer activity.

International patent application WO 2006/078886 describes 2,4-diaminopyrimidines substituted in the 6-position by an aryl group as wnt modulators. The 4-aryl group is lacking any substituents or must be substituted in the 3-position by methoxy. The document does not disclose or suggest compounds with any other substituent-pattern, nor does it mention or suggest the use of such compounds in the treatment of cancer. Moreover, in all examples the 4-amino group of the pyrimidine is substituted by either 1,3-benzodioxol-5-ylmethyl or by 4-hydroxy-phenethyl. Several scientific publications describe the use of one of the compounds (N4-(1,3-benzodioxol-5-ylmethyl)-6-(3-methoxyphenyl)-2,4-pyrimidinediamine) as a tool to investigate the wnt-pathway.

International patent application WO 86/04583 describes aziridinyl substituted anti-neoplastic compounds. There is only one compound that has both a 6-aryl substituent and a 4-N-alkyl group attached to 2-aminopyrimidine core. The compound has besides the aziridinyl group a fluorine in the 5-position of the pyrimidine ring. Both the aziridinyl and the fluorine are implied to be important for the activity and there is nothing that suggests that anti-neoplastic activity can be obtained without at least one of these substituents.

British patent application GB 681712 describes 2,4-diaminopyrimidines substituted in the 6-position by an aryl group for use in the treatment of cancer, but in only one example the aryl is phenyl and the 4-amino group is substituted by an alkyl. In this compound the phenyl is unsubstituted and the alkyl is methyl. There is no disclosure in this documents of compounds in which the 6-phenyl may be substituted by other groups than chloro or nitro in the para-position, that the 6-phenyl may contain more than one substituent or that the 4-alkylamino-group is larger than methyl or may carry substituents.

Two publications from the group of H. Junjappa (Indian Journal Chemistry (1985), 24B 466; Synthesis (1980), 748) describe the synthesis of certain 2-amino-4-(N-alkylamino)-6-arylpyrimidines. The publications do not mention or suggest the use of the synthesized compounds in the treatment of cancer.

There are numerous 2-amino-4-(N-alkylamino)-6-arylpyrimidines that are, or that at some point have been stated to be, commercially available but that do not have any ascribed pharmaceutical use, nor any other use, ascribed to them.

MTH1 inhibitors have been described in Streib, M. et al. Angewandte Chemie, Int, Ed. (2013), Vol. 52. The compounds are organometallic and are not 2-amino-4-(N-alkylamino)-6-arylpyrimidines.

SUMMARY OF THE INVENTION

Although the finding of oncogenes and development of new anticancer treatments and diagnosis have improved the life length of cancer patients, there is still a high medical need to find more effective and less toxic treatments for e.g. breast cancer, leukemia, colon or lung cancer. Our preliminary data suggests that MTH1 inhibitors have the potential to be very effective against cancer forms with dysfunctional redox status, with minimal general toxic effects. MTH1 inhibition may also be a suitable adjuvant therapy to be used in conjunction with radiotherapies or other chemotherapeutic approaches.

The present invention aims at providing new treatments for cancer that can be achieved by inhibition of MTH1

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Effect on cell survival following MTH1 siRNA depletion in various human cancer and normal cell lines.

FIG. 2. MTH1 inhibitor reduce cell survival in various cancer cell lines, with less effect on normal immortalised cells (VH10 and BJ hTERT)

DETAILED DESCRIPTION OF THE INVENTION

There is provided a compound of formula I,

for use in the treatment of cancer

wherein:

R¹ represents heteroaryl connected to the pyrimidine of formula I via a carbon atom of the heteroaryl ring, which heteroaryl ring is optionally substituted by one or more substituents selected from Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² and heterocycloalkyl optionally substituted by one or more Y³; or aryl represented by

E¹ represents hydrogen, Y^(1a), —C₁₋₆alkyl optionally substituted by one or more Y² or heterocycloalkyl optionally substituted by one or more Y³;

E² represents hydrogen, Y^(1b), —C₁₋₆alkyl optionally substituted by one or more Y² or heterocycloalkyl optionally substituted by one or more Y³;

E³ and E⁴ each independently represents hydrogen, Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² or heterocycloalkyl optionally substituted by one or more Y³;

R² represents hydrogen, halogen, —CN, —C₁₋₁₂alkyl optionally substituted by one or more Z¹, or heterocycloalkyl optionally substituted by one or more Z²;

R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z²; or

R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ and —C₁₋₉alkyl optionally substituted by one or more Z⁴;

each Y¹ independently represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

Y^(1a) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(px), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

Y^(1b) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(py), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k), R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independently represents hydrogen, —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(b) and R^(c), R^(e) and R^(f), R^(l) and R^(m) and/or R^(t) and R^(u) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two further heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(f), R^(j), R^(o), R^(r) and R^(px) independently represents C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

R^(py) represents hydrogen, —C₂₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³;

each Y² independently represents halogen, —CN, —C(O)R^(b1), —C(O)N(R^(d))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O;

each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O;

each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1), R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1) and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/or R^(u1) and R^(v1) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(g1), R^(k1), R^(p1) and R^(s1) independently represents —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³;

each Z¹ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶, or ═O;

each Z² and Z³ independently represents halogen, —R^(a2), —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each Z⁴ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, heteroaryl optionally substituted by one or more substituents selected from W⁶, or ═O;

each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2), R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(r2), R^(t2), R^(u2) and R^(v2) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; or

any two R^(c2) and R^(d2), R^(f2) and R^(g2), R^(m2) and R^(n2) and/or R^(u2) and R^(v2) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W⁵, C₁₋₃alkyl optionally substituted by one or more substituents selected from W⁴), and ═O;

each R^(g2), R^(k2), R^(p2) R^(q2) and R^(s2) independently represents C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each W¹ and W⁴ independently represents halogen, —CN, —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl optionally substituted by one or more substituents selected from G², or ═O;

each W², W³, W⁵ and W⁶ independently represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl (optionally substituted by one or more substituents selected from G², or ═O;

each W⁷, W⁸, W¹⁰ and W¹¹ independently represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²;

W⁹ represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²;

each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3), R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3) and R^(v3) independently represents hydrogen or C₁₋₆ alkyl optionally substituted by one or more G³; or

any two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/or R^(u3) and R^(v3) are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one heteroatom and which ring optionally is substituted by one or more G²;

each R^(g3), R^(k3), R^(p3), and R^(s3) independently represents C₁₋₆ alkyl optionally substituted by one or more G^(a);

R^(q3x) represents C₂₋₆ alkyl optionally substituted by one or more G³;

each G¹ and G² independently represents halogen, —R^(a4), —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4), R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4) and R^(v4) independently represents hydrogen or —C₁₋₆ alkyl optionally substituted by one or more —F; or

any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/or R^(u4) and R^(v4) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring is optionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃, —CH₂CF₃, or ═O;

each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆ alkyl optionally substituted by one or more —F;

each m independently represents 0, 1 or 2;

provided that formula I does not represent

-   6-(3-pyridinyl)-N⁴-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,4-pyrimidinediamine, -   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyridinyl]methyl]-2,4-pyrimidinediamine, -   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyrimidinyl]-methyl]-2,4-pyrimidinediamine     or -   N⁴-[2-(1-aziridinyl)ethyl]-5-fluoro-6-phenyl-2,4-pyrimidinediamine,

or a pharmaceutically acceptable salt thereof;

which compounds may be referred to herein as “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. For the avoidance of doubt, solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is the upper limit of the range) defined herein may (in a similar manner to the definition of C_(1-q) alkyl) be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkylene groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q)alkenylene or a C_(2-q)alkynylene group). Particular alkylene groups that may be mentioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyl group). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C_(2-q) (e.g. C_(4-q)) heterocycloalkenyl (where q is the upper limit of the range) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo-[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called “spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form. At each occurrence when mentioned herein, a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or 6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5- to 10-membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, or two rings, of which at least one is aromatic. Substituents on heteroaryl/heteroaromatic groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring. Examples of heteroaryl/heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl, indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides of heteroaryl/heteroaromatic groups are also embraced within the scope of the invention (e.g. the N-oxide). As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by the wiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ is represented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred features) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.

Particular compounds of formula I that may be mentioned include those in which:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one or more Z¹; and

R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include those in which R² represents methyl, or preferably, hydrogen and R³ represents:

-   (a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) optionally substituted by     two, or preferably, one Z¹ or -   (b) —C₂₋₆alkyl optionally substituted by two, or preferably, one Z¹     or heterocycloalkyl optionally substituted by two, or preferably,     one Z²; or -   (c) —C₁₋₂alkyl optionally substituted with one or more —F; or

-   (e) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroaryl     having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom     and which heteroaryl is optionally substituted by one or more     substituents selected from W³; or -   (f) a —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,     cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl,     cyclobutylethyl, cyclopropylpropyl, oxetanyl, tetrahydrofuryl,     tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,     piperazinyl or morpholinyl wherein the C₃₋₆alkyl is optionally     substituted by two, or preferably, one Z¹ and the heterocycloalkyl     is optionally substituted by two, or preferably, one Z².

Particular compounds of formula I that may be mentioned include those in which: R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ or —C₁₋₉alkyl optionally substituted by one or more Z⁴.

For example, compounds of formula I that may be mentioned include those in which R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 6-membered non-aromatic ring, wherein the non-aromaticring is:

-   (a) unsubstituted; or -   (b) substituted by one or more substituents selected from Z³; or -   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more     Z⁴; or -   (d) substituted by one or more substituents selected from Z³ and     substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those in which: E¹ is Y^(1a) or —C₁₋₆alkyl optionally substituted by one or more Y² and at least one of E², E³ and E⁴ represents Y^(1b) or —C₁₋₆alkyl optionally substituted by one or more Y².

Preferred compounds of formula I that may be mentioned include those in which: E¹ is Y^(1a) or —C₁₋₃alkyl optionally substituted by one or more Y² and at least one of E² and E⁴ represents Y^(1b), —C₁₋₃alkyl optionally substituted by one or more Y².

Particular compounds of formula I that may be mentioned include those in which R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuranyl, benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl, isoxazolyl, pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, isoxazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include those in which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl or indol-5-yl, where the indolyl is optionally substituted on the nitrogen with —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferably optionally substituted phenyl, e.g. unsubstituted phenyl or phenyl substituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Particular compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E², E³ and E⁴ represent hydrogen and

E¹ represents hydrogen, or more preferably —F, —Cl, —CH₃, —CF₃, CN or —OCH₃; or

E¹, E³ and E⁴ represent hydrogen and

E² represents —F, —Cl, —CH₃, —CF₃, —CH═CHC(O)OCH₃, —CH₂NH₂, —CN, —CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)N(H)(4-methylphenyl), —N(H)C(O)CH₃, —N(H)C(O)CH═CH₂, —N(H)C(O)CH═CHCH₂NMe₂, —N(H)C(O)CH═CHPh, —N(H)C(O)C≡CH, —N(H)C(O)(2-hydroxyphenyl), —N(H)C(O)(6-hydroxypyrid-2-yl), —N(H)C(O)(5-chloro-2-hydroxyphenyl), —N(H)C(O)CH₂CH₂C(O)(1-pyrrolidinyl), —N(H)C(O)CH₂(OH), —N(H)C(O)CH(OH)Ph, —N(H)C(O)C(O)CH₃, —N(H)C(O)C(O)Ph, —N(H)S(O)₂CH═CH₂, or —OCH₃; or

E¹, E² and E⁴ represent hydrogen and

E³ represent —F, —Cl, —CH₃, —CF₃, —C(CH₃)₃, —CH═CH₂, —CH═CHC(O)OH, —CH═CHC(O)OCH₃, —CH₂NH₂, —CN, —CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)H, C(O)CH₃, —C(O)CF₃, —C(O)N(H)CH₃, —C(O)N(H)CH₂(2-furanyl), —C(O)(4-morpholinyl), —C(O)OH, —C(O)OCH₃, —N(H)C(O)CH₃, —N(H)C(O)CH═CH₂, —N(H)S(O)₂CH₃, —OCH(CH₃)₂, —OCH₃, —OCF₃, —S(O)₂CH₃, or —S(O)₂(4-morpholinyl).

Other particular compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E³ and E⁴ represent hydrogen; and

E¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH₂; or

E² and E⁴ represent hydrogen; and

E¹ represents —F and E³ represents —F or phenyl; or

E¹ represents —Cl and E³ represents —F or —Cl; or

E¹ represents —CH₃ and E³ represents —Cl or —OCH₂phenyl; or

E¹ represents —OCH₃ and E³ represents —F; or

E² and E³ represent hydrogen; and

E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or

E¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; or

E¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃, —CN, —N(H)C(O)CH═CH₂ or —S(O)₂(4-morpholinyl); or

E¹ represents —CF₃ and E⁴ represents —F or —CF₃; or

E¹ represents —CN and E⁴ represents —Cl; or

E¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CN or —OCH₃; or

E¹ and E⁴ represent hydrogen; and

E² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; or

E² represents —Cl and E³ represents —F or —C(O)(4-morpholinyl); or

E² represents —CH₃ and E³ represents —F or —OCH₃; or

E¹ represents —OCH₃ and E³ represents —OH; or

E¹ represents —CH₂OCH₃ and E³ represents (piperidin-4-yl)methoxy or ((1-tertbutoxycarbonyl)piperidin-4-yl)methoxy; or

E¹ and E³ represent hydrogen; and

E² and E⁴ represent —F; or

E² and E⁴ represent —CF₃; or

E⁴ represents hydrogen; and

E¹, E² and E³ represent —F; or

E¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; or

E¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; or

E² and E³ represent —Cl and E¹ represents —CH₃; or

E² represents hydrogen; and

E¹, E³ and E⁴ represent —F; or

E³ and E⁴ represent —Cl and E¹ represents —CH₃; or

E¹ and E⁴ represent —Cl and E¹ represents —OCH₃; or

E¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; or

E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; or

E¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or

E¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or

E¹ and E⁴ represent —CH₃ and E³ represents —F; or

E¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃; or

E¹ represents hydrogen; and

E² and E⁴ represent —CH₃ and E³ represents —OH; or

E³ represents hydrogen; and

E¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred particular compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E¹, E³ and E⁴ represent hydrogen and

E² represents —CH═CHC(O)OCH₃, —CH₂NH₂, —CH₂N(H)C(O)CH═CH₂, —CH₂OH, —N(H)C(O)CH═CH₂, —N(H)C(O)CH═CHCH₂NMe₂, —N(H)C(O)CH═CHPh, —N(H)C(O)C≡CH, —N(H)C(O)CH₂(OH), —N(H)C(O)CH(OH)Ph, —N(H)C(O)C(O)CH₃, —N(H)C(O)C(O)Ph or —N(H)S(O)₂CH═CH₂; or

E¹, E² and E⁴ represent hydrogen and

E³ represents —CH═CH₂, —CH═CHC(O)OH, —CH═CHC(O)OCH₃, —CH₂NH₂, —CH₂N(H)C(O)CH═CH₂, —CH₂OH, —C(O)H, —C(O)CH₃, —C(O)CF₃, —N(H)C(O)CH═CH₂; or

E³ and E⁴ represent hydrogen; and

E¹ represents —F and E² represents —F, —Cl, or —CF₃; or

E¹ represents —Cl and E² represents —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E² represents —Cl, —CH₃, —CN or —N(H)C(O)CH═CH₂; or

E² and E⁴ represent hydrogen; and

E¹ and E³ represent —F; or

E¹ represents —Cl and E³ represents —F or —Cl; or

E¹ represents —CH₃ and E³ represents —Cl; or

E² and E³ represent hydrogen; and

E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or

E¹ represents —Cl and E⁴ represents —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E⁴ represent, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH; or

E¹ represents —CF₃ and E⁴ represents —F or —CF₃; or

E¹ represents —CN and E⁴ represents —Cl; or

E⁴ represents hydrogen; and

E¹, E² and E³ represent —F; or

E¹ and E² represent —CH₃ and E³ represents —F₃; or

E² and E³ represent —Cl and E¹ represents —CH₃; or

E² represents hydrogen; and

E¹, E³ and E⁴ represent —F; or

E³ and E⁴ represent —Cl and E¹ represents —CH₃; or

E¹ and E⁴ represent —CH₃ and E³ represents —F or —CH₃; or

E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; or

E¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or

E¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or

E¹ and E⁴ represent —CH₃ and E³ represents —F; or

E¹ represents —CH₃, E³ represents —CF₃ and E⁴ represents —Cl; or

E¹ represents hydrogen; and

E² and E⁴ represent —CH₃ and E³ represents —OH; or

E³ represents hydrogen; and

E¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those in which:

(a) Z¹ is not present or is selected from —F, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

or

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶; or

(b) Z² is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Other preferred compounds of formula I that may be mentioned include those in which:

(a) Z³ is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; and/or

(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Particularly preferred compounds of formula I that may be mentioned include those in which Z¹ represents —F, —CN, —C(O)NH₂, —C(O)N(R^(c2))R^(d2), —C(O)-(4-morpholinyl), —C(O)OEt, —N(H)C(O)Me, —N(H)C(O)R^(i2), —N(H)C(O)CH₂NMe₂, —N(H)C(O)OCMe₃, —N(H)C(O)OCH₂Ph, —N(Me)C(O)OCMe₃, —N(H)C(O)N(H)Me, —N(H)C(O)N(H)CHMe₂, —N(H)S(O)₂Me, —OMe, —OCF₃ and —OEt.

Preferred compounds of formula I where Z¹ represents heterocycloalkyl that may be mentioned are those where Z¹ represents dihydropyridinyl, imidazolinyl, morpholinyl, oxanyl, piperazinyl, piperidinyl, pyrrolidinyl and quinuclidinyl, wherein the heterocycloalkyl is optionally substituted by one or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independently represents hydrogen, halogen, —R^(a3) or —CN; and

one of W⁸ and W⁹ represents hydrogen, halogen, —R^(a3) or —CN and the other represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

Particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independently represents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen; and

one of W⁸ and W⁹ (preferably W⁸) represents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen, and the other (preferably W⁹) represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

For example, particular compounds of formula I that may be mentioned include those wherein:

(a) W⁸, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁷ represents —Cl or —S(O)₂CH₃; or

(b) W⁷, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁸ represents —F, —Br, —CN, —N(H)C(O)CH₃, —OCH₃ or —S(O)₂CH₃; or

(c) W⁷, W¹⁰ and W¹¹ represents hydrogen and:

-   -   (i) W⁸ and W⁹ represents —F or —Cl; or     -   (ii) W⁸ represents —F and W⁹ represents —CH₃.

More particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

For example, more particularly preferred compounds of formula I that may be mentioned are those where where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹ represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂, —S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl.

Preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazolyl, benzodioxinyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl and triazolyl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazol-2-yl, 1,4-benzo-dioxin-2-yl, benzoxazol-2-yl, furan-2-yl, imidazol-1-yl, imidazol-4-yl, imidazo-[1,2-a]pyridin-2-yl, indol-3-yl, indol-5-yl, isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl, thiophen-2-yl, 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

More particularly preferred compounds of formula I that may be mentioned are those where W⁶ represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In another embodiment of the invention there is provided a compound of formula I,

wherein:

R¹ represents:

indanyl, naphthyl, tetrahydronaphthyl or heteroaryl, the latter connected to the pyrimidine of formula I via a carbon atom of the heteroaryl ring, which indanyl, naphthyl, tetrahydronaphthyl and heteroaryl rings are optionally substituted by one or more substituents selected from Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² and heterocycloalkyl optionally substituted by one or more Y³; or aryl represented by

E¹, E², E³ and E⁴ represents hydrogen, Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² or heterocycloalkyl optionally substituted by one or more Y³, but where at least one of E¹, E², E³ and E⁴ is other than hydrogen;

R² represents hydrogen, halogen or —C₁₋₁₂alkyl optionally substituted by one or more Z¹;

R³ represents —C₁₋₁₂alkyl substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z²; or

R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ or —C₁₋₉alkyl optionally substituted by one or more Z⁴;

each Y¹ independently represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³;

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k), R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independently represents hydrogen, —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(b) and R^(c), R^(e) and R^(f), R^(i) and R^(m) and/or R^(t) and R^(u) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(f), R^(j), R^(o) and R^(r) independently represent —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

each Y² independently represents halogen, —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W²;

each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O;

each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1), R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), Rut and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/or R^(u1) and R^(v1) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(g1), R^(k1), R^(p1) and R^(s1) independently represent —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³;

each Z¹ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶;

each Z² and Z³ independently represents halogen, —R^(a2), —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each Z⁴ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, heteroaryl optionally substituted by one or more substituents selected from W⁶, or ═O;

each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2), R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(r2), R^(t2), R^(u2) and R^(v2) independently represents hydrogen or C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; or

any two R^(c2) and R^(d2), R^(f2) and R^(g2), R^(m2) and R^(n2) and/or R^(u2) and R^(v2) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W⁵, C₁₋₃alkyl optionally substituted by one or more substituents selected from W⁴, and ═O;

each R^(g2), R^(k2), R^(p2) R^(q2) and R^(s2) independently represent —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each W¹ and W⁴ independently represents halogen, —CN, —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl optionally substituted by one or more substituents selected from G², or ═O;

each W², W³, W⁵ and W⁶ independently represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl (optionally substituted by one or more substituents selected from G², or ═O;

W⁷ and W¹¹ represents hydrogen;

each W⁸ and W¹⁰ independently represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²;

W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²;

each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3), R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3) and R^(v3) independently represents hydrogen or —C₁₋₆ alkyl optionally substituted by one or more G³; or

any two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/or R^(u3) and R^(v3) are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one heteroatom and which ring optionally is substituted by one or more G²;

each R^(g3), R^(k3), R^(p3), R^(q3) and R^(s3) independently represent C₁₋₆ alkyl optionally substituted by one or more G³;

R^(q3x) represents C₂₋₆ alkyl optionally substituted by one or more G³;

each G¹ and G² independently represents halogen, —R^(a4), —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4), R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4) and R^(v4) independently represents hydrogen or —C₁₋₆ alkyl optionally substituted by one or more —F; or

any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/or R^(u4) and R^(v4) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃, —CH₂CF₃, or ═O;

each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆ alkyl optionally substituted by one or more —F;

each m independently represents 0, 1 or 2;

provided that formula I does not represent

-   6-(3-pyridinyl)-N⁴-[[4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl]methyl]-2,4-pyrimidinediamine, -   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyridinyl]methyl]-2,4-pyrimidinediamine, -   6-(3-pyridinyl)-N⁴-[[5-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]-2-pyrimidinyl]-methyl]-2,4-pyrimidinediamine, -   N⁴-[2-(diethylamino)ethyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine, -   N⁴-[3-(4-morpholinyl)propyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine,     or -   N⁴-[2-(4-morpholinyl)ethyl]-6-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;

or a pharmaceutically acceptable salt thereof;

which compounds may be referred to herein as “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. For the avoidance of doubt, solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is the upper limit of the range) defined herein may (in a similar manner to the definition of C_(1-q) alkyl) be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkylene groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q)alkenylene or a C_(2-q)alkynylene group). Particular alkylene groups that may be mentioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyl group). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C_(2-q) (e.g. C_(4-q)) heterocycloalkenyl (where q is the upper limit of the range) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called “spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form. At each occurrence when mentioned herein, a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or 6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5- to 10-membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, or two rings, of which at least one is aromatic. Substituents on heteroaryl/heteroaromatic groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring. Examples of heteroaryl/heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl, indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides of heteroaryl/heteroaromatic groups are also embraced within the scope of the invention (e.g. the N-oxide). As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by the wiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ is represented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred features) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.

Particular compounds of formula I that may be mentioned include those in which:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one or more Z¹; and

R³ represents —C₁₋₁₂alkyl substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include those in which R² represents methyl, or preferably, hydrogen and R³ represents:

-   (a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by two, or     preferably, one Z¹ or; -   (b) —C₂₋₆alkyl substituted by two, or preferably, one Z¹ or     heterocycloalkyl optionally substituted by two, or preferably, one     Z²; or

-   (d) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroaryl     having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom     and which heteroaryl is optionally substituted by one or more     substituents selected from W³; or -   (e) —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,     cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl,     cyclobutylethyl, cyclopropylpropyl, oxetanyl, tetrahydrofuryl,     tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl,     piperazinyl or morpholinyl wherein the C₃₋₆alkyl is substituted by     two, or preferably, one Z¹ and the heterocycloalkyl is optionally     substituted by two, or preferably, one Z².

Particular compounds of formula I that may be mentioned include those in which:

R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ or —C₁₋₉alkyl optionally substituted by one or more Z⁴.

For example, compounds of formula I that may be mentioned include those in which R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 6-membered non-aromatic ring, wherein the non-aromatic ring is:

-   (a) unsubstituted; or -   (b) substituted by one or more substituents selected from Z³; or -   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more     Z⁴; or -   (d) substituted by one or more substituents selected from Z³ and     substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those in which R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuranyl, benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl, pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include those in which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl or indol-5-yl, where the indolyl is optionally substituted on the nitrogen with —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferably optionally substituted phenyl, e.g. unsubstituted phenyl or phenyl substituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Preferred compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E², E³ and E⁴ represent hydrogen and

E¹ represents —F, —Cl, —CH₃, —CF₃, CN or —OCH₃; or

E¹, E³ and E⁴ represent hydrogen and E² represents —F, —Cl, —CH₃, —CF₃, —CN; or

E¹, E² and E⁴ represent hydrogen and E³ represent —F, —Cl, —CH₃, —CF₃, —C(CH₃)₃, —CH═CH₂, —OCF₃, —S(O)₂CH₃, or —S(O)₂(4-morpholinyl).

Other preferred compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E³ and E⁴ represent hydrogen; and

E¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃ or —CN; or

E² and E⁴ represent hydrogen; and

E¹ represents —Cl and E³ represents —F or —Cl; or

E¹ represents —CH₃ and E³ represents —Cl; or

E¹ represents —OCH₃ and E³ represents —F; or

E² and E³ represent hydrogen; and

E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or

E¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; or

E¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —CN; or

E¹ represents —CF₃ and E⁴ represents —F or —CF₃; or

E¹ represents —CN and E⁴ represents —Cl; or

E¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CN or —OCH₃; or

E¹ and E⁴ represent hydrogen; and

E² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; or

E² represents —Cl and E³ represents —F; or

E² represents —CH₃ and E³ represents —F or —OCH₃; or

E¹ represents —OCH₃ and E³ represents —OH; or

E¹ and E³ represent hydrogen; and

E² and E⁴ represent —F; or

E² and E⁴ represent —CF₃; or

E⁴ represents hydrogen; and

E¹, E² and E³ represent —F; or

E¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; or

E¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; or

E² and E³ represent —Cl and E¹ represents —CH₃; or

E² represents hydrogen; and

E¹, E³ and E⁴ represent —F; or

E³ and E⁴ represent —Cl and E¹ represents —CH₃; or

E¹ and E⁴ represent —Cl and E¹ represents —OCH₃; or

E¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; or

E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; or

E¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or

E¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or

E¹ and E⁴ represent —CH₃ and E³ represents —F; or

E¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃; or

E¹ represents hydrogen; and

E² and E⁴ represent —CH₃ and E³ represents —OH; or

E³ represents hydrogen; and

E¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those in which:

(a) Z¹ represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

or

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶; or

(b) Z² is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Other preferred compounds of formula I that may be mentioned include those in which:

(a) Z³ is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; and/or

(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

More particularly preferred compounds of formula I that may be mentioned include those in which Z¹ represents —F, —CN, —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

or

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶.

Other more particularly preferred compounds of formula I that may be mentioned include those in which Z¹ represents —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2) or aryl represented by

Further compounds of formula I that may be mentioned include those in which R^(c2), R^(f2), R^(h2), R^(l2), R^(m2), R^(o2), and R^(u2) represents hydrogen; and

R^(d2), R^(g2), R^(i2), R^(n2) R^(p2), R^(q2), R^(t2) and R^(v2) represents aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Preferred compounds of formula I that may be mentioned are those where where Z¹ represents —OR^(q2) and R^(q2) represents aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

More preferred compounds of formula I that may be mentioned are those where Z¹ represents —N(R^(f2))R^(g2), R^(f2) represents hydrogen and R^(g2) represents aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Further preferred compounds of formula I that may be mentioned are those where Z¹ represents —N(R^(o2))S(O)₂R^(p2), R^(o2) represents hydrogen and R^(p2) represents aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Preferred compounds of formula I where Z¹ represents heterocycloalkyl that may be mentioned are those where Z¹ represents dihydropyridinyl, imidazolinyl, oxanyl, piperazinyl, piperidinyl, pyrrolidinyl and quinuclidinyl, wherein the heterocycloalkyl is optionally substituted by one or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where:

(a) each W⁸ and W¹⁰ are independently selected from —F, —Cl, —CH₃, —CN, —CF₃, or more preferably hydrogen and W⁹ is selected from —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²; and

(b) each W⁹ and W¹⁰ are independently selected from —F, —Cl, —CH₃, —CN, —CF₃, or more preferably hydrogen and W⁸ is selected from —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

For example, particular compounds of formula I that may be mentioned include those wherein W⁸ and W¹⁰ represents hydrogen and W⁹ represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂, —S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl; or

W⁹ and W¹⁰ represents hydrogen and W⁸ represents —F, —Cl, —CN, —CH₃, —NMe₂, —S(O)₂NH₂ or —S(O)₂NMe₂.

Preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazolyl, benzodioxinyl, benzoxazolyl, imidazolyl, imidazopyridinyl, indolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl and triazolyl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazol-2-yl, 1,4-benzo-dioxin-2-yl, benzoxazol-2-yl, imidazol-1-yl, imidazol-4-yl, imidazo[1,2-a]pyridin-2-yl, indol-3-yl, indol-5-yl, isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl, thiophen-2-yl, 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

More particularly preferred compounds of formula I that may be mentioned are those where W⁶ represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In yet another embodiment of the invention there is provided a compound of formula I,

wherein:

R¹ represents heteroaryl connected to the pyrimidine of formula I via a carbon atom of the heteroaryl ring, which heteroaryl ring is substituted by one or more substituents selected from Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² and heterocycloalkyl optionally substituted by one or more Y³; or aryl represented by

E¹ represents Y^(1a) or —C₁₋₆alkyl optionally substituted by one or more Y²; and at least one of E², E³ and E⁴ represents Y^(1b) or —C₁₋₆alkyl optionally substituted by one or more Y²;

R² represents hydrogen, halogen, —CN, —C₁₋₁₂alkyl optionally substituted by one or more Z¹, or heterocycloalkyl optionally substituted by one or more Z²;

R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z²; or

R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ and —C₁₋₉alkyl optionally substituted by one or more Z⁴;

each Y¹ independently represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

Y^(1a) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(px), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

Y^(1b) represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k), R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independently represents hydrogen, —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(b) and R^(c), R^(e) and R^(f), R^(l) and R^(m) and/or R^(t) and R^(u) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two further heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(f), R^(j), R^(o), R^(r) and R^(px) independently represents C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³;

each Y² independently represents halogen, —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O;

each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O;

each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1), R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1) and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or

any two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/or R^(u1) and R^(v1) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O;

each R^(g1), R^(k1), R^(p1) and R^(s1) independently represents —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³;

each Z¹ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶, or ═O;

each Z² and Z³ independently represents halogen, —R^(a2), —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each Z⁴ independently represents halogen, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —OC(O)R^(r2), —OS(O)₂R^(s2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, heteroaryl optionally substituted by one or more substituents selected from W⁶, or ═O;

each R^(a2), R^(b2), R^(c2), R^(d2), R^(e2), R^(f2), R^(h2), R^(i2), R^(j2), R^(l2), R^(m2), R^(n2), R^(o2), R^(q2), R^(r2), R^(t2), R^(u2) and R^(v2) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; or

any two R^(c2) and R^(d2), R^(f2) and R^(g2), R^(m2) and R^(n2) and/or R^(u2) and R^(v2) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W⁵, C₁₋₃alkyl optionally substituted by one or more substituents selected from W⁴), and ═O;

each R^(g2), R^(k2), R^(p2) and R^(s2) independently represents C₁₋₆ alkyl optionally substituted by one or more substituents selected from W⁴, heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶;

each W¹ and W⁴ independently represents halogen, —CN, —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl optionally substituted by one or more substituents selected from G², or ═O;

each W², W³, W⁵ and W⁶ independently represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl (optionally substituted by one or more substituents selected from G², or ═O;

each W⁷, W⁸, W⁹, W¹⁹ and W¹¹ independently represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²;

each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3), R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3) and R^(v3) independently represents hydrogen or C₁₋₆ alkyl optionally substituted by one or more G³; or

any two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/or R^(u3) and R^(v3) are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one heteroatom and which ring optionally is substituted by one or more G²;

each R^(g3), R^(k3), R^(p3), R^(q3) and R^(s3) independently represents C₁₋₆ alkyl optionally substituted by one or more G^(a);

each G¹ and G² independently represents halogen, —R^(a4), —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O;

each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4), R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4) and R^(v4) independently represents hydrogen or C₁₋₆ alkyl optionally substituted by one or more —F; or

any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/or R^(u4) and R^(v4) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring optionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃, —CH₂CF₃, or ═O;

each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆ alkyl optionally substituted by one or more —F;

each m independently represents 0, 1 or 2;

provided that formula I does not represent

-   N⁴-cyclopropyl-6-(4-methoxy-2-methylphenyl)-2,4-pyrimidinediamine

or a pharmaceutically acceptable salt thereof;

which compounds may be referred to herein as “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin. For the avoidance of doubt, solvates are also included within the scope of the invention.

Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.

Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.

Unless otherwise specified, C_(1-q) alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkyl group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q) alkenyl or a C_(2-q) alkynyl group).

Unless otherwise specified, C_(1-q) alkylene groups (where q is the upper limit of the range) defined herein may (in a similar manner to the definition of C_(1-q) alkyl) be straight-chain or, when there is a sufficient number (i.e. a minimum of two or three, as appropriate) of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-q)-cycloalkylene group). When there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkylene groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C_(2-q)alkenylene or a C_(2-q)alkynylene group). Particular alkylene groups that may be mentioned include those that are straight-chained and saturated.

The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo (for example, fluoro and chloro).

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten and, most preferably, between three and eight, e.g. a 5- or 6-membered heterocycloalkyl group). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C_(2-q) (e.g. C_(4-q)) heterocycloalkenyl (where q is the upper limit of the range) or a C_(7-q) heterocycloalkynyl group. C_(2-q) heterocycloalkyl groups that may be mentioned include 7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo-[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called “spiro”-compound. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form. At each occurrence when mentioned herein, a heterocycloalkyl group is preferably a 3- to 8-membered heterocycloalkyl group (e.g. a 5- or 6-membered heterocycloalkyl group).

The term “aryl”, when used herein, includes C₆₋₁₄ (e.g. C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and, when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groups that may be mentioned include phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyl and the like). For the avoidance of doubt, the point of attachment of substituents on aryl groups may be via any carbon atom of the ring system.

The term “heteroaryl” (or heteroaromatic), when used herein, includes 5- to 10-membered heteroaromatic groups containing one or more heteroatoms selected from oxygen, nitrogen and/or sulfur. Such heteroaryl group may comprise one, or two rings, of which at least one is aromatic. Substituents on heteroaryl/heteroaromatic groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl/heteroaromatic groups may be via any atom in the ring system including (where appropriate) a heteroatom. Bicyclic heteroaryl/heteroaromatic groups may comprise a benzene ring fused to one or more further aromatic or non-aromatic heterocyclic rings, in which instances, the point of attachment of the polycyclic heteroaryl/heteroaromatic group may be via any ring including the benzene ring or the heteroaryl/heteroaromatic or heterocycloalkyl ring. Examples of heteroaryl/heteroaromatic groups that may be mentioned include pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, pyrimidinyl, indolyl, azaindolyl, pyrazinyl, indazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl and benzotriazolyl. The oxides of heteroaryl/heteroaromatic groups are also embraced within the scope of the invention (e.g. the N-oxide). As stated above, heteroaryl includes polycyclic (e.g. bicyclic) groups in which one ring is aromatic (and the other may or may not be aromatic). Hence, other heteroaryl groups that may be mentioned include e.g. benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetra-hydroquinolinyl and the like.

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulfur.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.

For the avoidance of doubt, when R¹ is defined as

it is connected to the rest of formula I by the bond interrupted by the wiggly line, and formula I can thus be represented by

Likewise, when R³ is —C₁₋₁₂ alkyl substituted by Z¹, and Z¹ is represented by

then, if e.g. R³ is C₂alkyl, then formula I can be represented by

The present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Hence, the compounds of the invention also include deuterated compounds, i.e. in which one or more hydrogen atoms are replaced by the hydrogen isotope deuterium.

All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred features) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.

Particular compounds of formula I that may be mentioned include those in which:

R² represents hydrogen or —C₁₋₁₂alkyl optionally substituted by one or more Z¹; and

R³ represents —C₁₋₁₂alkyl optionally substituted by one or more Z¹ or heterocycloalkyl optionally substituted by one or more Z².

For example, compounds of formula I that may be mentioned include those in which R² represents methyl, or preferably, hydrogen and R³ represents:

(a) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) optionally substituted by two, or preferably, one Z¹ or

(b) —C₂₋₆alkyl optionally substituted by two, or preferably, one Z¹ or heterocycloalkyl optionally substituted by two, or preferably, one Z²; or

(c) —C₁₋₂alkyl optionally substituted with one or more —F; or

(e) —C₁₋₁₂alkyl (for example —C₁₋₆alkyl) substituted by heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and which heteroaryl is optionally substituted by one or more substituents selected from W³; or

(f) a —C₃₋₆alkyl or a heterocycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopropylpropyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl wherein the C₃₋₆alkyl is optionally substituted by two, or preferably, one Z¹ and the heterocycloalkyl is optionally substituted by two, or preferably, one Z².

Particular compounds of formula I that may be mentioned include those in which:

R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 8-membered (e.g. a 5- to 6 membered) non-aromatic ring, wherein the link formed by R² and R³ is optionally substituted by one or more substituents selected from Z³ or —C₁₋₉alkyl optionally substituted by one or more Z⁴.

For example, compounds of formula I that may be mentioned include those in which R² and R³ are linked together to form, along with the atoms to which they are attached, a 5- to 6-membered non-aromatic ring, wherein the non-aromaticring is:

-   (a) unsubstituted; or -   (b) substituted by one or more substituents selected from Z³; or -   (c) substituted by —C₁₋₉alkyl optionally substituted by one or more     Z⁴; or -   (d) substituted by one or more substituents selected from Z³ and     substituted by —C₁₋₉alkyl optionally substituted by one or more Z⁴.

Particular compounds of formula I that may be mentioned include those in which:

R¹ represents

Preferred compounds of formula I that may be mentioned include those in which E¹ represents Y^(1a) or —C₁₋₆alkyl optionally substituted by one or more Y²; and at least one of E², E³ and E⁴ (preferably at least one of E² and E⁴) represents Y^(1b) or —C₁₋₆alkyl optionally substituted by one or more Y².

Particular compounds of formula I that may be mentioned include those in which R¹ represents heteroaryl.

Preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuranyl, benzothiophenyl, dihydrobenzofuranyl, indazolyl, indolyl, isoquinolinyl, isoxazolyl, pyridinyl, pyrrolyl and quinolinyl.

Particularly preferred compounds of formula I where R¹ represents heteroaryl that may be mentioned are those where R¹ represents benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, isoxazol-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-yl.

For example, compounds of formula I that may be mentioned include those in which R¹ represents indolyl, e.g. indol-3-yl, indol-4-yl or indol-5-yl, where the indolyl is optionally substituted on the nitrogen with —S(O)₂Ar^(x), where Ar^(x) is aryl or heteroaryl, preferably optionally substituted phenyl, e.g. unsubstituted phenyl or phenyl substituted in the 4-position by —F, —Cl, —CH₃ or —CF₃.

Particular compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E³ and E⁴ represent hydrogen; and

E¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E² represents —F, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH₂; or

E² and E⁴ represent hydrogen; and

E¹ represents —F and E³ represents —F or phenyl; or

E¹ represents —Cl and E³ represents —F or —Cl; or

E¹ represents —CH₃ and E³ represents —Cl or —OCH₂phenyl; or

E¹ represents —OCH₃ and E³ represents —F; or

E² and E³ represent hydrogen; and

E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or

E¹ represents —Cl and E⁴ represent —F, —Cl, —CH₃, —CF₃ or —OCH₃; or

E¹ represents —CH₃ and E⁴ represent —F, —Cl, —CH₃, —CF₃, —CN, —N(H)C(O)CH═CH₂ or —S(O)₂(4-morpholinyl); or

E¹ represents —CF₃ and E⁴ represents —F or —CF₃; or

E¹ represents —CN and E⁴ represents —Cl; or

E¹ represents —OCH₃ and E⁴ represents —F, —Cl, Br, —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CN or —OCH₃; or

E¹ and E⁴ represent hydrogen; and

E² represents —F and E³ represents —F, —Cl, —OH or —OCH₃; or

E² represents —Cl and E³ represents —F or —C(O)(4-morpholinyl); or

E² represents —CH₃ and E³ represents —F or —OCH₃; or

E¹ represents —OCH₃ and E³ represents —OH; or

E¹ represents —CH₂OCH₃ and E³ represents (piperidin-4-yl)methoxy or ((1-tertbutoxycarbonyl)piperidin-4-yl)methoxy; or

E¹ and E³ represent hydrogen; and

E² and E⁴ represent —F; or

E² and E⁴ represent —CF₃; or

E⁴ represents hydrogen; and

E¹, E² and E³ represent —F; or

E¹ and E² represent —Cl and E³ represents —Cl, —OH or —OCH₃; or

E¹ and E² represent —CH₃ and E³ represents —F or —OCH₃; or

E² and E³ represent —Cl and E¹ represents —CH₃; or

E² represents hydrogen; and

E¹, E³ and E⁴ represent —F; or

E³ and E⁴ represent —Cl and E¹ represents —CH₃; or

E¹ and E⁴ represent —Cl and E¹ represents —OCH₃; or

E¹ and E⁴ represent —CH₃ and E³ represents —F, —CH₃ or —OCH₃; or

E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; or

E¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or

E¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or

E¹ and E⁴ represent —CH₃ and E³ represents —F; or

E¹ represents —CH₃, E⁴ represents —Cl and E³ represents —CF₃ or —OCH₃; or

E¹ represents hydrogen; and

E² and E⁴ represent —CH₃ and E³ represents —OH; or

E³ represents hydrogen; and

E¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred particular compounds of formula I that may be mentioned include those in which R¹ is represented by

where:

E³ and E⁴ represent hydrogen; and

E¹ represents —F and E² represents —F, —Cl, or —CF₃; or

E¹ represents —Cl and E² represents —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E² represents —Cl, —CH₃, —CN or —N(H)C(O)CH═CH₂; or

E² and E⁴ represent hydrogen; and

E¹ and E³ represent —F; or

E¹ represents —Cl and E³ represents —F or —Cl; or

E¹ represents —CH₃ and E³ represents —Cl; or

E² and E³ represent hydrogen; and

E¹ represents —F and E⁴ represents —Cl, —CH₃ or —CN; or

E¹ represents —Cl and E⁴ represents —F, —Cl, —CH₃ or —CF₃; or

E¹ represents —CH₃ and E⁴ represent, —Cl, —CH₃, —CF₃, —CN or —N(H)C(O)CH═CH; or

E¹ represents —CF₃ and E⁴ represents —F or —CF₃; or

E¹ represents —CN and E⁴ represents —Cl; or

E⁴ represents hydrogen; and

E¹, E² and E³ represent —F; or

E¹ and E² represent —CH₃ and E³ represents —F₃; or

E² and E³ represent —Cl and E¹ represents —CH₃; or

E² represents hydrogen; and

E¹, E³ and E⁴ represent —F; or

E³ and E⁴ represent —Cl and E¹ represents —CH₃; or

E¹ and E⁴ represent —CH₃ and E³ represents —F or —CH₃; or

E¹ represents —F, E³ represents —CH₃ and E⁴ represents —Cl; or

E¹ represents —Cl, E³ represents —F and E⁴ represents —CH₃; or

E¹ represents —Cl, E³ represents —CH₃ and E⁴ represents —F; or

E¹ and E⁴ represent —CH₃ and E³ represents —F; or

E¹ represents —CH₃, E³ represents —CF₃ and E⁴ represents —Cl; or

E¹ represents hydrogen; and

E² and E⁴ represent —CH₃ and E³ represents —OH; or

E³ represents hydrogen; and

E¹ and E² represent —Cl and E⁴ represents —CH₃.

Preferred compounds of formula I that may be mentioned include those in which:

(a) Z¹ is not present or is selected from —F, —CN, —C(O)R^(b2), —C(O)N(R^(c2))R^(d2), —C(O)OR^(e2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl represented by

or

heteroaryl having 1 to 3 nitrogen atoms, one oxygen atom and/or one sulfur atom and optionally substituted by one or more substituents selected from W⁶; or

(b) Z² is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Other preferred compounds of formula I that may be mentioned include those in which:

(a) Z³ is not present or is selected from —F, —R^(a2), —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶; and/or

(b) Z⁴ is not present or is selected from —F, —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(j2))C(O)OR^(k2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))S(O)₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), heterocycloalkyl optionally substituted by one or more substituents selected from W⁵, aryl optionally substituted by one or more substituents selected from W⁶, or heteroaryl optionally substituted by one or more substituents selected from W⁶.

Particularly preferred compounds of formula I that may be mentioned include those in which Z¹ represents —F, —CN, —C(O)NH₂, —C(O)N(R^(c2))R^(d2), —C(O)-(4-morpholinyl), —C(O)OEt, —N(H)C(O)Me, —N(H)C(O)R^(i2), —N(H)C(O)CH₂NMe₂, —N(H)C(O)OCMe₃, —N(H)C(O)OCH₂Ph, —N(Me)C(O)OCMe₃, —N(H)C(O)N(H)Me, —N(H)C(O)N(H)CHMe₂, —N(H)S(O)₂Me, —OMe, —OCF₃ and —OEt.

Preferred compounds of formula I where Z¹ represents heterocycloalkyl that may be mentioned are those where Z¹ represents dihydropyridinyl, imidazolinyl, morpholinyl, oxanyl, piperazinyl, piperidinyl, pyrrolidinyl and quinuclidinyl, wherein the heterocycloalkyl is optionally substituted by one or more substituents selected from W⁵.

Preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independently represents hydrogen, halogen, —R^(a3) or —CN; and

one of W⁸ and W⁹ represents hydrogen, halogen, —R^(a3) or —CN and the other represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

Particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where each W⁷, W¹⁰ and W¹¹ independently represents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen; and

one of W⁸ and W⁹ (preferably W⁸) represents —F, —Cl, —CH₃, —CF₃, or more preferably, hydrogen, and the other (preferably W⁹) represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

For example, particular compounds of formula I that may be mentioned include those wherein:

(a) W⁸, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁷ represents —Cl or —S(O)₂CH₃; or

(b) W⁷, W⁹, W¹⁰ and W¹¹ represents hydrogen and W⁸ represents —F, —Br, —CN, —N(H)C(O)CH₃, —OCH₃ or —S(O)₂CH₃; or

(a) W⁷, W¹⁰ and W¹¹ represents hydrogen and:

-   -   (i) W⁸ and W⁹ represents —F or —Cl; or     -   (ii) W⁸ represents —F and W⁹ represents —CH₃.

More particularly preferred compounds of formula I where Z¹ represents

that may be mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².

For example, more particularly preferred compounds of formula I that may be mentioned are those where W⁷, W⁸, W¹⁰ and W¹¹ are hydrogen and W⁹ represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂, —S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-ylmethyl and 1,2,3-thiadiazol-4-yl.

Preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazolyl, benzodioxinyl, benzoxazolyl, furanyl, imidazolyl, imidazopyridinyl, indolyl, isoquinolinyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridyl, pyrrolopyridinyl, quinolinyl, thiazolyl, thiophenyl and triazolyl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

Particularly preferred compounds of formula I where Z¹ represents heteroaryl that may be mentioned are those where Z¹ represents benzimidazol-2-yl, 1,4-benzo-dioxin-2-yl, benzoxazol-2-yl, furan-2-yl, imidazol-1-yl, imidazol-4-yl, imidazo-[1,2-a]pyridin-2-yl, indol-3-yl, indol-5-yl, isoquinolin-4-yl, 1,3,4-oxadiazol-2-yl, 1,2-oxazol-4-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 5H,6H,7H-pyrrolo[3,4-b]pyridin-5-yl, thiazol-5-yl, thiophen-2-yl, 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl, wherein the heteroaryl is optionally substituted by one or more substituents selected from W⁶.

More particularly preferred compounds of formula I that may be mentioned are those where W⁶ represents —F, —Cl, —Br, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —SO₂CH₃, —SO₂NH₂ and —SO)₂N(CH₃)₂.

In one embodiment, the compound according to the invention is selected from the compounds of Examples 1-454

As discussed hereinbefore, compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined, for use as a pharmaceutical.

In another aspect of the invention the use of a compound of the invention, as hereinbefore defined, is provided for the manufacture of a medicament for the treatment of cancer.

Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the “active” compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention.

By “prodrug of a compound of the invention”, we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time, following enteral or parenteral administration (e.g. oral or parenteral administration). All prodrugs of the compounds of the invention are included within the scope of the invention.

Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the “active” compounds of the invention to which they are metabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds, which possess pharmacological activity.

It is stated herein that the compounds of the invention may be useful in the treatment of cancer. For the purposes of this specification, and for the avoidance of doubt, the term “treatment” includes treatment per se, prevention and prophylaxis.

In an alternative embodiment, compounds of the invention may be useful in the the treatment of cancer.

Preferably the cancer is selected from the group comprising: Soft Tissue Cancers: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood and bone marrow (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids; neurofibromatosis and Adrenal glands: neuroblastoma. The term “cancerous cell” as provided herein, includes a cell afflicted by any one of the above identified conditions.

In certain embodiments of the present invention, the cancer is a solid tumor cancer.

In certain embodiments of the present invention, the cancer is selected from pancreatic cancer, ovarian cancer and colorectal cancer.

In certain embodiments of the present invention, the cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, and glioma.

In certain embodiments of the present invention, the cancer is selected from non-small cell lung cancer, ovarian cancer, metastatic breast cancer, pancreatic cancer, hepatobiliary cancer (including hepatocellular cancer, bile duct cancer and cholangiocarcinoma), and gastric cancer.

In certain embodiments of the present invention, the cancer is selected from colorectal cancer (including Ras mutations), small cell lung cancer, non-small cell lung cancer, ovarian cancer, hepatobiliary cancer (including hepatocellular cancer, bile duct cancer and cholangiocarcinoma), gastric cancer, testicular cancer, and head and neck squamous cell carcinoma.

In certain embodiments of the present invention, the cancer is selected from leukemia (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia), lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), and prostate cancer

Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intranasally, topically, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.

Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical compositions/formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.

Compounds of the invention (i.e. compounds that inhibit MTH1) may be administered in the form of tablets or capsules, e.g., time-release capsules that are taken orally. Alternatively, the compounds of the invention may be in a liquid form and may be taken orally or by injection. The compounds of the invention may also be in the form of suppositories, or, creams, gels, and foams e.g. that can be applied to the skin. In addition, they may be in the form of an inhalant that is applied nasally.

Such compositions/formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided a pharmaceutical composition/formulation including a compound of the invention, as hereinbefore defined, optionally in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier. Such compositions/formulations may be of use in the treatment, prevention and/or prophylaxis of cancer and diseases which benefit by inhibition of MTH1.

Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

In yet another aspect the present invention provides methods for the treatment of cancer comprising administering a therapeutically effective amount of a compound of the invention to a subject (e.g. patient) in need of such treatment.

“Patients” include mammalian (including human) patients.

The term “effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).

Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of cancer.

According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of the invention, as hereinbefore defined; and

(B) another therapeutic agent that is useful in the in the treatment of cancer, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of cancer, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(2) a kit of parts comprising components:

-   -   (a) a pharmaceutical formulation including a compound of the         invention, as hereinbefore defined, in admixture with a         pharmaceutically-acceptable adjuvant, diluent or carrier; and     -   (b) a pharmaceutical formulation including another therapeutic         agent that is useful in the treatment of cancer in admixture         with a pharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of cancer, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.

By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit of parts may be:

(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or

(ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.

Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages (and subcutaneous dosages, although these dosages may be relatively lower) may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day.

For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 2000 mg, for example between about 0.1 mg to about 500 mg, or between 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise. In particular, compounds of the invention may have the advantage that they are more efficacious and/or exhibit advantageous properties in vivo.

It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

EXAMPLES

The invention is illustrated by way of the following examples, in which the following abbreviations may be employed.

-   aq aqueous -   DMF dimethylformamide -   DMSO dimethyl sulfoxide -   EtOAc ethyl acetate -   EtOH ethanol -   MeOH methanol -   MeCN acetonitrile -   Pd—C palladium on carbon -   sat. saturated -   TFA trifluoroacetic acid -   THF tetrahydrofuran -   min. minutes -   h. hours -   Hunigs base N,N-diisopropylethylamine -   DCM dichloromethane -   n-BuOH butan-1-ol -   iPrOH propan-2-ol -   NEt₃ trethylamine -   Boc tert-butoxycabonyl -   HATU     (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo-[4,5-b]pyridinium     3-oxid hexafluorophosphate -   NMP N-methylpyrrolidine -   LCMS liquid-chromatography electrospray mass spectroscopy -   NMR nuclear magnetic resonance -   NCS N-chlorosuccinimide -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium (0) -   B(OMe)₃ trimethylborate -   n-BuLi n-butyl lithium -   MeI iodomethane -   NaOMe sodium methoxide -   CHCl₃ chloroform -   MgSO₄ anhydrous magnesium sulphate -   K₂CO₃ anhydrous potassium carbonate -   NH₄OH ammonium hydroxide -   Ac₂O acetic anhydride -   POCl₃ phosphorus oxychloride

Starting materials and chemical reagents specified in the syntheses described below are commercially available, e.g. from Sigma-Aldrich, Fine Chemicals Combi-Blocks and other vendors.

In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context). Final compounds were named using Marvin software version 6.1.

Purification of compounds may be carried out using silica gel column chromatography or preparative reverse phase HPLC (ACE column, acidic gradients with MeCN—H₂O containing 0.1% TFA or XBridge column, basic gradients using MeCN—H₂O containing ammonium bicarbonate) to give the products as their free bases or trifluoroacetic acid salts.

Intermediate 1 (7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid

Step 1: 6-bromo-4-chloro-2H-1,3-benzodioxole

To a solution of 5-bromo-2H-1,3-benzodioxole (60 μL, 0.50 mmol, 1 eq.) in acetonitrile (1 mL) was added 1-chloropyrrolidine-2,5-dione (73 mg, 0.55 mmol, 1.1 eq.). The reaction was stirred overnight at room temperature. After completion of the reaction, the reaction mixture was concentrated and purified by column chromatography (Heptane/EtOAc 100%→5:1) to afford the desired product as a colourless solid (104 mg, 89%). LCMS [M+H]⁺ 234; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.05 (1H, s), 6.93 (1H, s), 2.78 (2H, s).

Step 2: (7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid

To a solution of 6-bromo-4-chloro-2H-1,3-benzodioxole (104 mg, 0.44 mmol, 1 eq.) in THF (5.8 mL) was added, at −78° C., n-BuLi (2.5 M in hexanes, 265 μL, 0.66 mmol, 1.5 eq.). The reaction mixture was stirred at this temperature for 30 min, before addition of B(OMe)₃ (248 μL, 2.21 mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HCl was added, and stirring was continued for 1 h. The reaction mixture was extracted with EtOAc, and the organic layer was dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (Pentane/EtOAc 100%→3:1) to afford the desired product as a white solid (22 mg, 25%). LCMS [M+H]⁺ 201; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.34 (1H, s), 6.81 (1H, s), 5.99 (2H, s).

Intermediate 2 2,3-dichloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

To a solution of 4-bromo-2,3-dichlorophenol (250 mg, 1.03 mmol, 1 eq.) in THF (10 mL) was added, at −78° C., n-BuLi (2.5 M in hexanes, 1.25 mL, 3.10 mmol, 3 eq.). The reaction mixture was stirred at this temperature for 30 min, before addition of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (316 μL, 1.55 mmol, 1.5 eq.). The reaction was slowly allowed to warm up to rt, 2N HCl was added, and stirring was continued for 1 h. The reaction mixture was extracted with EtOAc, and the organic layer was dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (Pentane/EtOAc 100%→4:1) to afford the desired product as a white solid (102 mg, 34%). LCMS [M+H]⁺ 289; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.47 (1H, d, J=8.1 Hz), 6.85 (1H, d, J=8.1 Hz), 1.36 (12H, s).

Intermediate 3 (2,3-dichloro-4-methoxyphenyl)boronic acid

Step 1: 4-Bromo-2,3-dichlorophenol

To a solution of 2,3-dichlorophenol (1.0 g, 6.13 mmol, 1 eq.) in DCM (4 mL) was added, at 0° C., bromine (348 μL, 6.75 mmol, 1.1 eq.) over 15 min. The reaction was allowed to warm up to rt over 12 hours. NMR showed unreacted starting material, bromine (0.33 eq.) was added at 0° C. and the reaction was allowed to warm up to rt over 12 hours. The reaction was stopped by addition of Na₂S₂O₃, the organic layer was washed with brine, dried with MgSO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (Pentane/EtOAc 100%→25:1) to afford the desired product as a white solid (685 mg, 46%). LCMS [M+H]⁺ 239; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 10.98 (1H, s), 7.54 (1H, d, J=8.8 Hz), 6.91 (1H, d, J=8.8 Hz).

Step 2: 1-Bromo-2,3-dichloro-4-methoxybenzene

To a solution of 4-bromo-2,3-dichlorophenol (200 mg, 0.83 mmol, 1 eq.) in DMF (3 mL) was added Cs₂CO₃ (538 mg, 1.65 mmol, 2 eq.) followed by iodomethane (208 μL, 3.3 mmol, 4 eq.). The reaction mixture was stirred at 70° C. for 3 h. The reaction was stopped by addition of H₂O, extracted with DCM, dried with MgSO₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (Pentane/EtOAc 100%→20:1) to afford the desired product as a white solid (190 mg, 89%). LCMS [M+H]⁺ 256; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.47 (1H, d, J=9.0 Hz), 6.73 (1H, d, J=8.8 Hz), 3.88 (3H, s).

Step 3: (2,3-dichloro-4-methoxyphenyl)boronic acid

To a solution of 1-bromo-2,3-dichloro-4-methoxybenzene (100 mg, 0.39 mmol, 1 eq.) in THF (5 mL) was added, at −78° C., n-BuLi (2.5 M in hexanes, 234 μL, 0.59 mmol, 1.5 eq.). The reaction mixture was stirred at this temperature for 30 min, before addition of B(OMe)₃ (218 μL, 1.95 mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HCl was added, and stirring was continued for 1 h. The reaction mixture was extracted with EtOAc, and the organic layer was dried over MgSO₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (Pentane/EtOAc 100%→3:1) to afford the desired product as a white solid (52 mg, 59%). LCMS [M+H]⁺ 221; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.25 (1H, s), 7.35 (1H, d, J=8.1 Hz), 7.10 (1H, d, J=8.1 Hz), 3.87 (3H, s).

Intermediate 4 (2,3-dichloro-5-methoxyphenyl)boronic acid

Step 1: 1-Bromo-3-chloro-5-methoxybenzene

1-Bromo-3-chloro-5-fluorobenzene (1 g, 4.77 mmol, 1 eq.) was treated at 0° C. with sodium methoxide (25% in MeOH, 1.2 mL, 5.71 mmol, 1.2 eq.). The reaction mixture was stirred at 100° C. for 3 h. The solution was concentrated under reduced pressure, the crude product was extracted with DCM, washed with H₂O, brine, dried over MgSO₄ and concentrated. The product was obtained as a white solid (747 mg, 71%). LCMS [M+H]⁺ 220; ¹H NMR (400 MHz, CD₃Cl) δ_(H) 7.09 (1H, t, J=1.7 Hz), 6.94-6.92 (1H, m), 6.83-6.80 (1H, m), 3.77 (3H, s).

Step 2: 1-Bromo-2,3-dichloro-5-methoxybenzene

To a solution of 1-bromo-3-chloro-5-methoxybenzene (300 mg, 1.35 mmol, 1 eq.) in DMF (5 mL) was added trichloro-1,3,5-triazinane-2,4,6-trione (115 mg, 0.49 mmol, 0.36 eq.) and the reaction was stirred at 50° C. for 3 h. The reaction mixture was concentrated and the crude product was purified by column chromatography (Heptane/EtOAc 100%→20:1) to afford the desired product as a white solid (253 mg, 73%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, CD₃Cl) δ_(H) 7.09 (1H, d, J=3.0 Hz), 6.97 (1H, d, J=3.0 Hz), 3.77 (3H, s).

Step 3: (2,3-dichloro-5-methoxyphenyl)boronic acid

To a solution of 1-bromo-2,3-dichloro-5-methoxybenzene (87 mg, 0.34 mmol, 1 eq.) in THF (4.5 mL) was added, at −78° C., n-BuLi (2.5 M in hexanes, 205 μL, 0.51 mmol, 1.5 eq.). The reaction mixture was stirred at this temperature for 30 min, before addition of B(OMe)₃ (191 μL, 1.70 mmol, 5 eq.). The reaction was slowly allowed to warm up to rt, 2N HCl was added, and stirring was continued for 1 h. The reaction mixture was extracted with EtOAc, and the organic layer was dried over MgSO₄ and evaporated under reduced pressure to afford the desired product as a white solid (75 mg, 100%). LCMS [M+H]⁺ 221.

Intermediate 5 4-chloro-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

Step 1: ethyl 2-ethoxy-3,4,5,6-tetrahydropyridine-3-carboxylate

To a solution of ethyl 2-oxopiperidine-3-carboxylate (1.5 g, 8.76 mmol, 1 eq.) in DCM (6.5 mL) under N₂ was added a solution of triethyloxonium tetrafluoroborate (2.0 g, 10.51 mmol, 1.2 eq.) in DCM (6.5 mL). The reaction mixture was stirred at room temperature overnight. The solution was poured in water (5 mL) and allowed to stand for 30 min. The organic layer was washed with NaHCO₃, H₂O, dried over Na₂SO₄ and concentrated under reduced pressure to afford the desired product as a colourless oil (1.2 g, 66%). ¹H NMR (400 MHz, CDCl₃) δ_(H) 4.15 (2H, q, J=7.2 Hz), 4.00-3.98 (2H, m), 3.46-3.44 (2H, m), 3.18-3.16 (1H, m), 1.97-1.95 (2H, m), 1.68-1.66 (1H, m), 1.49-1.47 (1H, m), 1.25 (3H, t, J=7.1 Hz), 1.20 (3H, t, J=7.0 Hz).

Step 2: 2-amino-3H,4H,5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-4-one

A solution of sodium ethoxide (21% in EtOH, 197 μL, 2.51 mmol, 2.5 eq.) was added to the mixture of ethyl 2-ethoxy-3,4,5,6-tetrahydropyridine-3-carboxylate (200 mg, 1 mmol, 1 eq.) and guanidine hydrochloride (96 mg, 1 mmol, 1 eq.) in EtOH (2 mL). The reaction mixture was stirred a reflux overnight. The solvent were removed under vacuum and the obtained solid was dried to afford the desired product as a light yellow solid (116 mg, 70% yield). ¹H NMR (400 MHz, CDCl₃) δ_(H) 9.89 (1H, br s), 6.18 (1H, br s), 6.10 (2H, br s), 3.10-3.08 (2H, m), 2.20-2.18 (2H, m), 1.61-1.59 (2H, m).

Step 3: 4-chloro-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

A mixture of 2-amino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4(3H)-one and acetic anhydride was heated at reflux for 1 h until completion of the reaction as monitored by LCMS. The solvent was removed under reduced pressure and the obtained residue was treated with benzyltriethylammonium chloride (547 mg, 2.4 mmol, 2 eq.) and POCl₃ (671 μL, 7.2 mmol, 6 eq.) and heated at reflux for 1 h. After evaporation of the solvents, ice water was added to the residue and HCl (6N, 5.5 mL) was added. The reaction mixture was heated at 50° C. overnight. After evaporation of the solvents, the residue is diluted in EtOAc and washed with NaHCO₃, brine and dried over Na₂SO₄. The combined organic layers were then evaporated, and the crude product was purified by column chromatography (DCM/MeOH 98/2 200 mL, 95/5 100 mL). The pure product was obtained as a yellow powder (45 mg, 20%). LCMS [M+H]⁺ 185. ¹H NMR (400 MHz, CDCl₃) δ_(H) 8.09-8.03 (1H, br s), 3.28-3.26 (2H, m), 2.53-2.51 (2H, m), 1.81-1.79 (2H, m).

Intermediate 6 4-chloro-6-phenylpyrimidin-2-amine

A mixture of 2-amino-4,6-dichloropyrimidine (3 g, 18.29 mmol, 1 eq.), phenylboronic acid (2.45 g, 20.12 mmol, 1.1 eq.), K₂CO₃ (5.06 g, 36.6 mmol, 2 eq.) and Pd(PPh₃)₄ (700 mg, 0.6 mmol, 0.03 eq.) in 1,4-dioxane (15 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 12 h. The mixture was run through a plug of silica using EtOAc as eluent, concentrated and purified by column chromatography (1:4 EtOAc/pentane) to give the desired product as a white solid (2.2 g, 60%). LCMS [M+H]⁺ 206; ¹H NMR (400 MHz, CDCl₃) δ_(H) 8.27-8.20 (2H, m), 8.16-8.05 (3H, m), 7.19 (2H, s), 6.76 (1H, s).

Intermediate 7 6-chloro-4-N-propylpyrimidine-2,4-diamine

A solution of 4,6-dichloropyrimidin-2-amine (820 mg, 5.0 mmol, 1 eq.) in EtOH (40 mL) was treated with propan-1-amine (5.0 ml). The reaction mixture was stirred at 85° C. for 48 h. The mixture was cooled, concentrated by evaporation then flash-chromatographed over silica to afford the product as a colorless solid (705 mg; 76%). LCMS [M+H]⁺ 187.

Intermediate 8 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (820 mg, 5.0 mmol, 1 eq.) in n-BuOH (20 mL) was added tert-butylamine (365 mg, 5.0 mmol, 1 eq.) and Hünig's base (645 mg, 5.0 mmol, 1 eq.). The reaction mixture was stirred overnight at 95° C. The mixture was cooled and some unreacted starting material removed by filtration. The filtrate was concentrated and the residue flash-chromatographed over silica to afford the product (0.27 g; 27%). LCMS [M+H]⁺ 201.

Intermediate 9 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (492 mg, 3.0 mmol, 1 eq.) in n-BuOH (20 mL) was added tetrahydro-2H-pyran-4-amine (303 mg, 3.0 mmol, 1 eq.) and Hünig's base (387 mg, 3.0 mmol, 1 eq.). The reaction mixture was stirred overnight at 95° C. The mixture was cooled the precipitated solid was collected and washed with water to give the product (0.42 g; 37%). LCMS [M+H]⁺ 229.

Intermediate 10 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.0 mmol, 1 eq.) in n-BuOH (5 mL) were added cyclopropanamine (80 μL, 1.1 mmol, 1.1 eq.) and Hünig's base (260 μL, 1.5 mmol, 1.5 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as an off-white solid (152 mg, 82%). LCMS [M+H]⁺ 185; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.29 (1H, s), 6.38 (2H, s), 5.85 (1H, s), 3.52 (1H, s), 0.73-0.64 (2H, m), 0.53-0.35 (2H, m).

Intermediate 11 6-chloro-4-N-(1-methoxybutan-2-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.1 mmol, 1 eq.) in n-BuOH (10 mL) were added 1-methoxybutan-2-amine (315 mg, 3.1 mmol, 1 eq.) and Hünig's base (531 μL, 3.1 mmol, 1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as an off-white solid (592 mg, 84%). LCMS [M+H]⁺ 231.

Intermediate 12 6-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.00 mmol, 1 eq.) in n-BuOH (5 mL) were added 2,2,2-trifluoroethanamine hydrochloride (149 mg, 1.1 mmol, 1.1 eq.) and NEt₃ (202 mg, 2.0 mmol, 2 eq.). The reaction mixture was stirred overnight at 90° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a yellow solid (59 mg, 26%). LCMS [M+H]⁺ 227.

Intermediate 13 6-chloro-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (164 mg, 1.00 mmol, 1 eq.) in n-BuOH (5 mL) were added 2,2-difluoroethanamine hydrochloride (129 mg, 1.1 mmol, 1.1 eq.) and triethylamine (202 mg, 2.0 mmol, 2 eq.). The reaction mixture was stirred overnight at 90° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a yellow solid (80 mg, 38%). LCMS [M+H]⁺ 209.

Intermediate 14 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.04 mmol, 1 eq.) in n-BuOH (10 mL) were added 2,2-difluoroethanamine hydrochloride (229 μL, 3.04 mmol, 1 eq.) and Hünig's base (584 μL, 3.35 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a yellow solid (471 mg, 84%). LCMS [M+H]⁺ 185.

Intermediate 15 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.04 mmol, 1 eq.) in n-BuOH (10 mL) were added cyclopentanamine (301 μL, 3.04 mmol, 1 eq.) and Hünig's base (584 μL, 3.35 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a brown foam (620 mg, quantitative). LCMS [M+H]⁺ 213.

Intermediate 16 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq.) in n-BuOH (5 mL) were added cyclobutanamine (130 μL, 1.52 mmol, 1 eq.) and Hünig's base (292 μL, 1.72 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid (248 mg, 80%). LCMS [M+H]⁺ 199.

Intermediate 17 6-iodo-4-N-methylpyrimidine-2,4-diamine

To a suspension of 6-Chloro-4-N-methylpyrimidine-2,4-diamine (1.5 g, 9.43 mmol, 1 eq.) in acetone (6.2 mL) was added sodium iodide (7.9 g, 52.8 mmol, 5.6 eq.) and hydrogen iodide (15 mL). The reaction mixture was stirred at 60° C. for 12 h. The solid was filtered off, dissolved in EtOAc, washed with NaHCO₃, brine, dried over MgSO₄ and concentrated under reduced pressure to afford the desired compound as an orange solid (1.7 g, 73%). LCMS [M+H]⁺ 251; ¹H NMR (400 MHz, CDCl₃) δ_(H) 6.27 (1H, s), 2.80 (3H, s).

Intermediate 18 6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (66 mg, 0.40 mmol, 1 eq.) in n-BuOH (2.5 mL) were added 2-phenylethanamine (75 μL, 0.60 mmol, 1.1 eq.) and Hünig's base (100 μg, 0.60 mmol, 1.1 eq.). The reaction mixture was stirred at 95° C. for 3 h. The solvent was removed in vacuo. The crude product was diluted in EtOAc and washed with H₂O, brine, dried over MgSO₄ and concentrated to afford the desired product as a yellow solid (88 mg, 88%). LCMS [M+H]⁺ 249.

Intermediate 19 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine

A mixture of 2-amino-4,6-dichloropyrimidine (0.82 g, 5.0 mmol, 1 eq.), 2,3-dimethylphenylboronic acid (0.75 g, 5.0 mmol, 1 eq.), K₂CO₃ (1.38 g, 10.0 mmol, 2 eq.) and palladium tetrakis(triphenylphosphine)palladium (0) (0.12 g, 0.10 mmol, 0.1 eq.) in 1,4-dioxane (20 mL) and water (5 mL) was heated in a sealed tube at 90° C. for 2.5 hours. The mixture was run through a plug of silica using EtOAc as eluent, concentrated and purified by column chromatography (1:4 EtOAc/pentane) to give the desired product as a white solid (0.76 g, 65%). LCMS [M+H]⁺ 234; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.21-7.29 (1H, m), 7.20-7.09 (2H, m), 6.70 (1H, s), 2.34 (3H, s), 2.23 (3H, s).

Intermediate 20 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine

A mixture of 4,6-dichloropyrimidin-2-amine (3.28 g, 20.0 mmol), methanamine (12.0 mL, 24.0 mmol; as a 2 M solution in methanol) and Hünig's base in n-butanol (20 mL) was heated at 95° C. overnight. The mixture was concentrated and the crude was taken up in EtOAc (300 mL) and washed with water (3×150 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the desired product as a buff solid (2.90 g, 91%). LCMS [M+H]⁺ 159.

Intermediate 21 6-chloro-4-N-methylpyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol), (2,3-dichlorophenyl)boronic acid (0.64 g, 3.35 mmol), sodium carbonate (0.65 g, 6.10 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (0.088 g, 0.076 mmol) in 1,4-dioxane/water (30 mL; 4:1) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was run through a plug of silica (EtOAc) and then concentrated. Purification by column chromatography (1:4→1:3 EtOAc/hexane) afforded the desired product as a white solid (0.26 g, 31%). LCMS [M+H]⁺ 274; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 6.89 (1H, s) 7.33 (2H, br s) 7.44-7.52 (2H, m) 7.71-7.81 (1H, m).

Intermediate 22 6-Chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (0.50 g, 3.05 mmol), 2-(4-chlorophenyl)ethan-1-amine (0.56 mL, 3.96 mmol) and Hünig's base (0.80 mL, 4.57 mmol) in n-butanol (5 mL) was heated in a sealed tube at 95° C. overnight. The mixture was concentrated and the crude was taken up in EtOAc (50 mL) and washed with water (3×40 mL). The organic layer was dried over MgSO4, filtered and concentrated to give the desired product as a buff solid (0.61 g, 71%). LCMS [M+H]⁺ 283.

Intermediate 23 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one

A mixture of 4,6-dichloropyrimidin-2-amine (1.64 g, 10.0 mmol), 1-(3-aminopropyl)pyrrolidin-2-one (1.96 mL, 14.0 mmol) and Hünig's base (2.61 mL, 15.0 mmol) in n-butanol (20 mL) was heated in a sealed tube at 110° C. overnight. The mixture was concentrated and the crude was taken up in EtOAc (300 mL) and washed with water (3×150 mL). The aqueous layers were combined and extracted with EtOAc (2×200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to give the desired product as a buff solid (1.63 g, 60%). LCMS [M+H]⁺ 270.

Intermediate 24 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine

A stirred mixture of 2-amino-4,6-dichloropyrimidine (0.50 g, 3.1 mmol), 3-chloro-2-methylphenylboronic acid (0.57 g, 3.4 mmol), Na₂CO₃ (1.0 g, 9.8 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (88 mg, 0.076 mmol), dioxane (22 mL) and water (8 mL) were heated in a sealed tube at 90° C. for 2 hours. The solvents were removed in vacuo and the remaining solid was added EtOAc (20 mL) and washed with water. The organic phase was dried over MgSO₄ and removed in vacuo. The crude material was purified by flash chromatography (1:4 EtOAc/petroleum ether) to give the desired product as a white solid (365 mg, 47%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 7.52-7.56 (1H, dd, J₁=6.5 Hz, J₂=2.5 Hz) 7.30-7.33 (2H, m) 7.26 (2H, s) 6.79 (1H, s) 2.32 (3H, s).

Intermediate 25 4-{2-[(2-amino-6-chloropyrimidin-4-yl)amino]ethyl}benzene-1-sulfonamide

To a suspension of 4,6-dichloropyrimidin-2-amine (800 mg, 4.9 mmol) and 4-(2-aminoethyl)benzenesulfonamide (980 mg, 4.9 mmol) in 2-propanol (10 mL), was added Hünig's base (1.0 mL, 5.7 mmol) and the resulting mixture was heated at reflux for 15 h. The mixture was then poured into NaHCO₃ (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated and the crude mixture was purified by column chromatography to afford the title compound. LCMS [M+H]⁺ 328; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.80-7.85 (m, 2H), 7.41 (d, J=8.6 Hz, 2H), 5.76-5.81 (m, 1H), 3.54-3.64 (m, 2H), 2.95 (t, J=7.1 Hz, 2H).

Intermediate 26 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine

A mixture of 4,6-dichloropyrimidin-2-amine (82 mg, 0.50 mmol), (2,3,4-trichlorophenyl)-boronic acid (113 mg, 0.50 mmol), potassium carbonate (138 mg, 1.0 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.013 mmol) in 1,4-dioxane/water (8 mL; 4:1) was heated in a sealed tube at 90° C. for 2 h. The reaction mixture was run through a plug of silica (EtOAc) and then concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 308.

Intermediate 27 6-chloro-4-N-ethylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (1 g, 6.09 mmol, 1 eq.) in n-BuOH (18 mL) were added ethaneamine (2M, 3.0 mL, 6.09 mmol, 1 eq.) and Hünig's base (1.17 mL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. Ethaneamine (1 eq) was added and the reaction was stirred overnight at 95° C. until complete consumption of starting material (2 additions). The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid. LCMS [M+H]⁺ 173; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.76 (1H, s), 4.79 (3H, br s), 3.26 (2H, br s), 1.20 (3H, t, J=7.2 Hz).

Intermediate 28 6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (1 g, 6.09 mmol, 1 eq.) in n-BuOH (18 mL) were added cyclohexanamine (698 μL, 6.09 mmol, 1 eq.) and Hünig's base (1.17 mL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. Cyclohexanamine (1 eq) was added and the reaction was stirred overnight at 95° C. until complete consumption of starting material (2 additions). The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid. LCMS [M+H]⁺ 227; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.73 (1H, s), 4.97 (2H, s), 4.79 (1H, br s), 3.45 (1H, br s), 1.97-1.92 (2H, m), 1.74-1.69 (2H, m), 1.63-1.58 (1H, m), 1.39-1.32 (2H, m), 1.22-1.10 (2H, m).

Intermediate 29 6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq.) in n-BuOH (4.5 mL) were added cyclopropylmethanamine (131 μL, 6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid. LCMS [M+H]⁺ 199; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.75 (1H, s), 4.92 (3H, br s), 3.07 (2H, s), 1.04-0.96 (1H, m), 0.55-0.49 (2H, m), 0.23-0.19 (2H, m).

Intermediate 30 6-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq.) in n-BuOH (4.5 mL) were added (1R)-1-cyclopropylethan-1-amine (141 μL, 6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a colourless oil (321 mg, 99%). LCMS [M+H]⁺ 213; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.71 (1H, s), 4.97 (2H, s), 4.86 (1H, br s), 3.23 (1H, s), 1.19 (3H, d, J=6.4 Hz), 0.89-0.81 (1H, m), 0.52-0.41 (2H, m), 0.31-0.25 (1H, m), 0.23-0.18 (1H, m).

Intermediate 31 6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05 mmol, 1 eq.) in n-BuOH (9 mL) were added propan-2-amine (262 μL, 6.09 mmol, 1 eq.) and Hünig's base (584 μL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid (569 mg, 99%). LCMS [M+H]⁺ 187; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.74 (1H, s), 4.76 (2H, s), 4.60 (1H, br s), 3.85 (1H, br s), 1.19 (3H, s), 1.18 (3H, s).

Intermediate 32 6-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq.) in n-BuOH (4.5 mL) were added (1S)-1-cyclopropylethan-1-amine (141 μL, 6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a colourless oil (296 mg, 91%). LCMS [M+H]⁺ 213; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.71 (1H, s), 4.99 (2H, s), 4.89 (1H, br s), 3.23 (1H, s), 1.19 (3H, d, J=6.4 Hz), 0.88-0.81 (1H, m), 0.50-0.40 (2H, m), 0.31-0.25 (1H, m), 0.23-0.17 (1H, m).

Intermediate 33 6-chloro-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4,6-dichloropyrimidin-2-amine (500 mg, 3.0 mmol), 2-(4-methylsulfonylphenyl)ethanamine (600 mg, 3.0 mmol) and Hünig's base (0.63 mL, 3.6 mmol) in 2-propanol (10 mL) was heated at reflux for 15 h. The reaction mixture was poured into NaHCO₃ (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated. The crude mixture was purified by column chromatography which afforded the title compound. LCMS [M+H]+ 327; ¹H NMR (400 MHz, CDCl3) δ ppm 7.90 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 5.77 (s, 1H), 4.80-4.89 (m, 2H), 4.69-4.79 (m, 1H), 3.56-3.67 (m, 2H), 3.07 (s, 3H), 3.00 (t, J=6.8 Hz, 2H).

Intermediate 34 6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

To a solution of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq.) in n-BuOH (9 mL) were added 2,2-dimethylpropan-1-amine (6.09 mmol, 1 eq.) and Hünig's base (292 μL, 6.70 mmol, 1.1 eq.). The reaction mixture was stirred overnight at 95° C. The solvent was removed in vacuo. The crude product was taken up in EtOAc and H₂O. The aqueous layer was extracted twice with EtOAc and once with CHCl₃/^(i)PrOH (3:1). The combined organic layers were washed with brine, dried over MgSO₄ and concentrated to afford the desired product as a white solid. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, CDCl₃) δ_(H) 5.94 (1H, s), 3.24 (2H, br s), 0.98 (9H, s).

Intermediate 35 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Step 1: To a suspension of 4,6-dichloropyrimidin-2-amine (500 mg, 3.05 mmol) and Hünig's base (0.80 mL) in 2-propanol (3.0 mL) was added tert-butyl N-(2-aminoethyl)carbamate (586 mg, 3.66 mmol) and the mixture was stirred at 150° C. for 15 min. The crude mixture was poured into NaHCO3 (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (0→10% MeOH in DCM) afforded tert-butyl N-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (850 mg, 2.95 mmol).

Step 2: tert-Butyl N-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]carbamate (850 mg, 2.95 mmol), (2,3-dimethylphenyl)boronic acid (532 mg, 3.55 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.030 mmol), and K₂CO₃ (1020 mg, 7.39 mmol) were suspended in 1,4-dioxane (10 ml) and H₂O (2.0 ml). The vial was flushed with nitrogen and the resulting mixture was stirred at 90° C. for 16 h. The crude mixture was poured into NaHCO3 (aq) and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (0→10% MeOH in DCM) afforded tert-butyl N-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]ethyl]carbamate (770 mg, 2.15 mmol).

Step 3: tert-Butyl N-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]ethyl]carbamate (770 mg, 2.15 mmol) was dissolved in TFA (6 mL) and the resulting mixture was stirred for 1 h at rt, after which the TFA was distilled off. Purification by column chromatography (5→30% MeOH [containing 1 v/v % NH₄OH] in DCM) afforded 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (500 mg, 1.94 mmol). LCMS [M+H]⁺ 258.

Intermediate 36 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Step 1: A vial was charged with 4,6-dichloropyrimidin-2-amine (500 mg, 3.0 mmol) and tert-butyl N-(2-aminopropyl)carbamate (640 mg, 3.7 mmol). Then 2-propanol (3.0 ml) and Hünig's base (0.80 ml) were added and the resulting mixture was heated at 150° C. using microwave irradiation for 15 min. The mixture was then concentrated and purified by column chromatography (2→10% MeOH in DCM) to afford tert-butyl N-[3-[(2-amino-6-chloro-pyrimidin-4-yl)amino]propyl]-carbamate (788 mg, 2.61 mmol).

Step 2: tert-Butyl N-[3-[(2-amino-6-chloro-pyrimidin-4-yl)amino]propyl]carbamate (790 mg, 2.6 mmol), (2,3-dimethylphenyl)boronic acid (470 mg, 3.1 mmol), palladium tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.050 mmol), and K₂CO₃ (720 mg 5.2 mmol) were suspended in 1,4-dioxane (6.0 ml) and H₂O (1.5 ml). The resulting mixture was heated at 90° C. for 16 h and then poured into H₂O and extracted three times with DCM. The combined organic layers were dried and concentrated. Purification by column chromatography (1→10% MeOH in DCM) afforded tert-butyl N-[3-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]propyl]carbamate (800 mg, 2.1 mmol).

Step 3: tert-Butyl N-[3-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]propyl]carbamate (800 mg, 2.1 mmol) was dissolved in TFA and heated at reflux for 1 h. The TFA was evaporated and the crude residue was purified by column chromatography (2→30% MeOH [containing 1 v/v % NH₄OH] in DCM) to afford 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (540 mg, 2.0 mmol). LCMS [M+H]⁺ 272.

Intermediate 37 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (250 mg, 1.52 mmol, 1 eq) in dioxane/H₂O (5 mL, 4:1) was added (2-chloro-3-methylphenyl)boronic acid (260 mg, 1.52 mmol, 1 eq) followed by potassium carbonate (421 mg, 3.05 mmol, 2 eq) and Pd(PPh₃)₄ (44 mg, 0.04 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12 hrs. The solvent was removed in vacuo. The residue was taken up in DMF and purified by preparative to afford the desired product as an off-white solid (166 mg, 43%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.32-7.28 (2H, m), 7.25-7.21 (1H, m), 6.92 (1H, s), 5.31 (2H, br s), 2.42 (3H, s).

Intermediate 38 4-chloro-6-(quinolin-5-yl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1 eq) in dioxane/H₂O (5 mL, 4:1) was added (quinolin-5-yl)boronic acid (158 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd(PPh₃)₄ (26 mg, 0.020 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12 hrs. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford the desired product as a yellow solid (63 mg, 27%). LCMS [M+H]⁺ 257; ¹H NMR (400 MHz, CDCl₃) δ_(H) 9.21-9.19 (2H, m), 8.62 (1H, d, J=8.8 Hz), 8.30-7.99 (1H, m), 7.92 (1H, dd, J=7.2 and 0.8 Hz), 7.81-7.77 (1H, m), 6.98 (1H, s), 5.40 (2H, br s).

Intermediate 39 4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1 eq) in dioxane/H₂O (5 mL, 4:1) was added (1H-indol-4-yl)boronic acid (147 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd(PPh₃)₄ (26 mg, 0.02 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12 hrs. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford the desired product as a yellow solid (111 mg, 50%). LCMS [M+H]⁺ 245; ¹H NMR (400 MHz, CDCl₃) δ_(H) 8.45 (1H, br s), 7.57 (1H, d, J=7.2 Hz), 7.51 (1H, d, J=8.0 Hz), 7.35 (1H, t, J=4.0 Hz), 7.27 (1H, d, J=7.6 Hz), 7.18 (1H, s), 7.00-6.99 (1H, m), 5.90 (2H, br s).

Intermediate 40 4-chloro-6-(5-chloro-2-methylphenyl)pyrimidin-2-amine

To a suspension of 4,6-dichloropyrimidin-2-amine (150 mg, 0.91 mmol, 1 eq) in dioxane/H₂O (5 mL, 4:1) was added (5-chloro-2-methylphenyl)boronic acid (155 mg, 0.91 mmol, 1 eq) followed by potassium carbonate (253 mg, 1.83 mmol, 2 eq) and Pd(PPh₃)₄ (26 mg, 0.02 mmol, 0.025 eq). The resulting mixture was stirred at 90° C. for 12 hrs. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford the desired product as an off-white solid (98 mg, 42%). LCMS [M+H]⁺ 254; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.35 (1H, d, J=2.0 Hz), 7.28 (1H, dd, J=8.4 and 2.4 Hz), 7.18 (1H, d, J=8.4 Hz), 6.72 (1H, s), 5.30 (2H, br s), 2.34 (3H, s).

Intermediate 41 6-(3-aminophenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.00 mmol), (3-aminophenyl)boronic acid (1.3 eq.), sodium carbonate (3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90° C. for 5 h and then concentrated. The crude material was taken up in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography (0→15% MeOH in DCM) to give the title compound. LCMS [M+H]⁺ 216.

Intermediate 42 6-(3-amino-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.00 mmol), (3-amino-2-methylphenyl)boronic acid (1.3 eq.), sodium carbonate (3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL). The tube was sealed and the reaction was heated at 90° C. for 5 h. The mixture was concentrated and purified by column chromatography (13% MeOH in DCM) to give the title compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.88 (1H, t, J=7.71 Hz), 6.71-6.81 (1H, m), 6.61 (1H, dd, J=7.96, 1.14 Hz), 6.44 (1H, dd, J=7.58, 1.01 Hz), 5.90 (2H, br. s.), 5.64 (1H, s), 4.83 (2H, s), 2.75 (3H, d, J=4.55 Hz), 1.98 (3H, s).

Intermediate 43 6-(5-amino-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (3.0 mmol), (5-amino-2-methylphenyl)boronic acid (1.3 eq.), sodium carbonate (3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90° C. for 5 h. The mixture was concentrated and purified by column chromatography (13% MeOH in DCM) to give the title compound. LCMS [M+H]⁺ 230.

Intermediate 44 6-(4-aminophenyl)-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.0 mmol), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.3 eq.), sodium carbonate (3.2 eq.), 1,4-dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90° C. for 5 h and then concentrated. The crude material was taken up in ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate, concentrated and purified by flash chromatography (0→15% MeOH/DCM) to give the title compound. LCMS [M+H]⁺ 216; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.64 (2H, d, J=8.53 Hz), 6.50-6.62 (3H, m), 6.03 (1H, s), 5.74 (2H, s), 5.37 (2H, s), 2.76 (3H, d, J=4.77 Hz).

General Procedures

General Procedure 1:

To a mixture of 4-chloro-6-phenylpyrimidin-2-amine (1 equiv.) is added Hünig's base (3.4 equiv.) and an appropriate amine (1.6 equiv.) in DMF (500 μL). The mixture is heated at 120° C. overnight. The crude mixture is purified by preparative HPLC to afford the desired product.

General Procedure 2:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) in 1,4-dioxane/water (4:1) is added the appropriate boronic acid (or boronic ester) derivative (1.3 equiv.), K₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The mixture is heated at 95° C. overnight or in a microwave reactor until the reaction is complete as shown by LCMS. The crude mixture is purified by preparative HPLC to afford the desired product.

General Procedure 3:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) is added Hünig's base (3.4 equiv.) and an appropriate amine (1.6 equiv.) in n-BuOH (500 μL). The mixture is heated at 95° C. overnight. The crude mixture was purified by preparative HPLC to afford the desired product.

General Procedure 4:

A solution of an appropriate chloropyrimidine derivative (1 equiv.) in ammonium hydroxide (25% aq.) is heated in the microwave at 120° C. until completion of the reaction as monitored by LCMS. The solvent is then evaporated and the product is dried under vacuum. Further purification by preparative HPLC is performed when required.

General Procedure 5:

To a mixture of a suitable chloropyrimidine derivative (1 equiv.) in DMF/water (9:1) is added the appropriate boronic acid (or boronic ester) derivative (1.1 equiv.), Na₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The mixture is heated at 120° C. overnight or in the microwave until the reaction is complete as shown by LCMS. The crude mixture is then purified by preparative HPLC to afford the desired product.

General Procedure 6:

To a mixture of a suitable iodopyrimidine derivative (1 equiv.) in DMF/water (20:1) is added the appropriate boronic acid (or boronic ester) derivative (1.3 equiv.), Na₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The mixture is heated at 120° C. overnight or in a microwave reactor until the reaction is complete as shown by LCMS. The crude mixture is then purified by HPLC to afford the desired product.

General Procedure 7:

A mixture of a suitable 6-aryl-4-chloropyrimidin-2-amine (1 equiv.), a suitable amine (1.5 equiv.) and triethylamine (2 equiv.) in n-butanol (1.5 mL) is heated in a sealed tube at 95° C. overnight. Concentrated and purified by preparative HPLC to give the desired product.

General Procedure 8:

To a mixture of a suitable 4-chloropyrimidin-2-amine (1 equiv.) in 1,4-dioxane/water (4:1) is added the desired boronic acid (or boronic ester) (1.3 equiv.), K₂CO₃ (2 equiv.) and Pd(PPh₃)₄ (0.1 equiv.). The mixture is heated at 95° C. overnight or in a microwave until the reaction is complete as shown by LCMS. The crude mixture is purified by HPLC to afford the desired product.

General Procedure 9:

A mixture of a suitable amine (1 equiv.), and a suitable chloropyrimidine derivative (1.2 equiv.) and triethylamine (1.5 equiv.) in 2-propanol (1.0 mL) is heated in a sealed tube at 95° C. overnight or at 150° C. for 15 min in a microwave reactor. The reaction mixture is then concentrated and purified by preparative HPLC or by silica gel chromatography.

General Procedure 10:

A mixture of an 4-N-(aminoalkyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0 equiv.), a suitable sulfonyl chloride (1.2 equiv.), and triethylamine (1.5 equiv.) in DCM or MeCN (1.0 mL) is stirred in a sealed tube at rt or 50° C. After completion the crude mixture is concentrated and purified by preparative HPLC or by silica gel chromatography.

General Procedure 11:

A mixture of 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0 eq.) and the corresponding isocyanate (1.05 eq.) is dissolved in DCM. The resulting reaction mixture is stirred at rt until completion according to LCMS. The mixture is then concentrated and purified by preparative HPLC or by silica gel chromatography.

General Procedure 12:

A mixture of 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0 equiv.) and the corresponding heteroaryl chloride (1.5 equiv.), and Hünig's base (1.5 equiv.) in 2-propanol (0.5 mL) is stirred in a sealed tube at 150° C. in a microwave reactor for 30 min. The crude mixture is then concentrated and purified by preparative HPLC or by silica gel chromatography.

EXAMPLES

The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the cancer cell clonogenic and/or viability assay described below. The link between activity in tumor cell clonogenic assay and anti-tumor activity in the clinical setting has been well established in the art (e.g. see ref Silverstini et al Stem Cells 1993, 11(6), 258-35).

Example 1 4-N-cyclohexyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclohexanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.79-8.61 (1H, m), 7.78-7.67 (2H, m), 7.66-7.55 (3H, m), 6.33 (1H, s), 4.05-3.85 (1H, m), 2.00-1.83 (2H, m), 1.80-1.70 (2H, m), 1.41-1.10 (6H, m).

Example 2 4-N-ethyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from ethanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.82 (1H, s), 7.74-7.71 (2H, m), 7.67-7.57 (3H, m), 6.33 (1H, s), 3.53-3.41 (2H, m), 1.18 (3H, t, J=7.1 Hz).

Example 3 4-N-(3-ethoxypropyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from 3-ethoxypropan-1-amine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.82 (1H, s), 7.74-7.71 (2H, m), 7.63-7.59 (3H, m), 6.37 (1H, s), 3.45-3.41 (6H, m), 1.80 (2H, q, J=6.5 Hz), 1.11 (3H, t, J=6.5 Hz).

Example 4 6-phenyl-4-N-propylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from phenylboronic acid and 6-chloro-4-N-propylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229.

Example 5 6-(4-methanesulfonylphenyl)-4-N-propylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methane-sulfonylphenyl)boronic acid and 6-chloro-4-N-propylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 307; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.21-8.11 (2H, m), 8.05-7.92 (2H, m), 6.42 (1H, s), 3.50-3.40 (2H, m), 3.31 (3H, s), 1.68-1.51 (2H, m), 0.94 (3H, t, J=7.1 Hz).

Example 6 4-N-(cyclopropylmethyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclopropylmethanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 241; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.92 (1H, s), 7.83-7.50 (5H, m), 6.39 (1H, s), 3.33-3.20 (2H, m), 1.15-0.95 (1H, m), 0.51 (1H, d, J=5.8 Hz), 0.27 (1H, d, J=5.8 Hz).

Example 7 4-N-(oxan-4-yl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from oxan-4-amine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 271.

Example 8 4-N-(furan-2-ylmethyl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from furan-2-ylmethanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 267.

Example 9 4-N-(pentan-3-yl)-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from pentan-3-amine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 257.

Example 10 6-phenyl-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 1 from propan-2-amine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 229.

Example 11 4-N-benzyl-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from phenylmethanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 277; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.92-7.84 (2H, m), 7.48-7.40 (4H, m), 7.37-7.27 (4H, m), 7.27-7.20 (1H, m), 6.29 (1H, s), 6.06 (2H, s), 4.54 (2H, d, J=5.9 Hz).

Example 12 4-N-[2-(morpholin-4-yl)ethyl]-6-phenylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from 2-(morpholin-4-yl)ethan-1-amine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 300.

Example 13 6-(4-chlorophenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 1 from cyclopropanamine and 4-chloro-6-phenylpyrimidin-2-amine. LCMS [M+H]⁺ 261.

Example 14 4-N-tert-butyl-6-(4-chlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 277; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.38 (1H, s), 7.75-7.66 (4H, m), 6.38 (1H, s), 1.46 (9H, s).

Example 15 6-(4-chlorophenyl)-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronic acid and 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 305.

Example 16 4-N-cyclopropyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(trifluoromethyl)phenyl]-boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 295.

Example 17 4-N-tert-butyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.65 (2H, d, J=9.4 Hz), 7.15 (2H, d, J=9.4 Hz), 6.35 (1H, s), 3.85 (3H, s), 1.45 (9H, s).

Example 18 4-N-cyclopropyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 7.79-7.72 (2H, m), 7.17-7.15 (2H, m), 6.24 (1H, s), 3.85 (4H, s), 0.83-0.81 (2H, m), 0.62-0.60 (2H, m).

Example 19 6-(3-chlorophenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 261; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.78-7.76 (1H, m), 7.64-7.57 (3H, m), 6.27 (1H, s), 0.89-0.87 (2H, m), 0.70-0.63 (3H, m).

Example 20 4-N-tert-butyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(trifluoromethyl)phenyl]boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 311.

Example 21 6-(3-chlorophenyl)-4-N-(oxan-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronic acid and 6-chloro-4-N-(oxan-4-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 305; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.78-7.76 (1H, m), 7.65-7.63 (2H, m), 7.59-7.57 (1H, m), 6.30 (1H, s), 4.30-4.28 (1H, m), 4.02-3.98 (2H, m), 3.53-3.51 (2H, m), 2.01-2.00 (2H, m), 1.65-1.63 (2H, m).

Example 22 4-N-tert-butyl-6-(3-chlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 277; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.73 (1H, m), 7.65-7.62 (2H, m), 7.59-7.55 (2H, m), 1.52 (9H, s).

Example 23 4-N-methyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 394; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.07 (1H, d, J=8.3 Hz), 7.93 (2H, d, J=8.3 Hz), 7.83 (1H, d, J=7.9 Hz), 7.51-7.44 (1H, m), 7.43-7.31 (3H, m), 6.46 (1H, s), 3.04 (3H, s), 2.37 (3H, s).

Example 24 6-(2,3-dichlorophenyl)-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dichlorophenyl)boronic acid and 6-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 337.

Example 25 6-(3-chlorophenyl)-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronic acid and 6-chloro-4-N-(2,2,2-trifluoroethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 303.

Example 26 6-[1-(benzenesulfonyl)-1H-indol-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(benzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 8.43-8.25 (2H, m), 8.10-8.03 (2H, m), 8.01-7.95 (1H, m), 7.77-7.68 (1H, m), 7.66-7.56 (2H, m), 7.46-7.26 (2H, m), 6.74 (1H, br s), 6.32 (1H, s), 6.02 (2H, s), 2.81 (3H, d, J=5.0 Hz).

Example 27 4-N-cyclopropyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 420; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.07 (1H, d, J=7.9 Hz), 8.01 (1H, d, J=8.2 Hz), 7.86 (2H, d, J=8.2 Hz), 7.43-7.23 (4H, m), 6.43 (1H, s), 2.65 (1H, s), 2.34 (3H, s), 0.88-0.74 (2H, m), 0.65-0.48 (2H, m).

Example 28 6-[1-(benzenesulfonyl)-1H-indol-3-yl]-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(benzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 406; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.16 (1H, s), 8.10-7.98 (4H, m), 7.66-7.58 (1H, m), 7.56-7.46 (2H, m), 7.43-7.25 (2H, m), 6.43 (1H, s), 2.66 (1H, s), 0.84-0.81 (2H, m), 0.58-0.55 (2H, m).

Example 29 6-[1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 381; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.55 (1H, d, J=8.2 Hz), 8.41-8.30 (2H, m), 8.22-8.11 (2H, m), 7.71-7.61 (1H, m), 7.57-7.50 (2H, m), 7.37-7.28 (1H, m), 6.27 (1H, s), 2.92 (3H, s).

Example 30 6-[1-(benzenesulfonyl)-1H-indol-4-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(benzenesulfonyl)-1H-indol-4-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.08 (1H, d, J=8.2 Hz), 7.97-7.89 (2H, m), 7.73 (1H, d, J=3.8 Hz), 7.65-7.56 (1H, m), 7.53-7.45 (3H, m), 7.39 (1H, t, J=8.2 Hz), 7.10 (1H, d, J=3.8 Hz), 6.10 (1H, s), 2.89 (3H, s).

Example 31 6-[1-(benzenesulfonyl)-1H-indol-5-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(benzenesulfonyl)-1H-indol-5-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 380; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.07-7.99 (2H, m), 7.98-7.89 (2H, m), 7.83-7.74 (1H, m), 7.71 (1H, d, J=4.0 Hz), 7.64-7.55 (1H, m), 7.54-7.45 (2H, m), 6.80 (1H, d, J=4.0 Hz), 6.21 (1H, s), 2.90 (3H, s).

Example 32 6-(2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2-methoxyphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.50 (1H, dd, J=7.5 and 1.7 Hz), 7.41-7.36 (1H, m), 7.08 (1H, d, J=8.3 Hz), 7.01 (1H, td, J=7.5 and 1.0 Hz), 6.17 (1H, s), 3.84 (3H, s), 2.89 (3H, s).

Example 33 6-(4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231.

Example 34 6-[3,5-bis(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3,5-bis(trifluoromethyl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, CD₃OD) δ_(H)8.31 (2H, s), 8.17 (1H, s), 7.55-7.20 (3H, br s), 6.45 (1H, s), 3.02 (3H, s).

Example 35 6-(isoquinolin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (isoquinolin-4-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 252; ¹H NMR (400 MHz, CD₃OD) δ_(H) 9.17 (1H, s), 8.78 (1H, s), 8.17 (1H, d, J=8.4 Hz), 8.12 (1H, d, J=8.1 Hz), 7.98-7.94 (1H, m), 7.80-7.77 (1H, m), 6.54 (1H, s), 3.10 (3H, s).

Example 36 4-N-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [4-(trifluoromethyl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.93-7.87 (4H, m), 6.38 (1H, s), 3.04 (3H, s).

Example 37 4-N-methyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(trifluoromethyl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.05 (1H, s), 7.99 (1H, d, J=8.0 Hz), 7.92 (1H, d, J=8.0 Hz), 7.79 (1H, t, J=8.0 Hz), 6.38 (1H, s), 3.05 (3H, s).

Example 38 6-(2,3-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from methanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.79-7.77 (1H, m), 7.50-7.49 (2H, m), 6.12 (1H, s), 3.04 (3H, s).

Example 39 6-(2H-1,3-benzodioxol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2H-1,3-benzodioxol-5-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.42-7.39 (1H, m), 7.36-7.35 (1H, m), 6.89 (1H, d, J=8.0 Hz), 6.15 (1H, s), 6.02 (1H, s), 2.92 (3H, s).

Example 40 3-[2-amino-6-(methylamino)pyrimidin-4-yl]benzonitrile

Prepared according to general procedure 2 from (3-cyanophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 226; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.15 (1H, s), 8.05-8.03 (1H, m), 7.95-7.92 (1H, m), 7.74 (1H, t, J=8.5 Hz), 6.35 (1H, s), 3.02 (3H, s).

Example 41 N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}acetamide

Prepared according to general procedure 2 from (3-acetamidophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.20 (1H, s), 7.56-7.52 (2H, m), 7.45-7.43 (1H, m), 6.31 (1H, s), 3.06 (3H, s), 2.19 (3H, s).

Example 42 4-N-methyl-6-[4-(morpholine-4-sulfonyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [4-(morpholine-4-sulfonyl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 350; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.99 (4H, s), 6.42 (1H, s), 3.76-3.72 (4H, m), 3.07 (3H, s), 3.06-3.03 (4H, m).

Example 43 6-(4-methanesulfonylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methanesulfonyl-phenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.20-8.17 (2H, m), 8.00-7.97 (2H, m), 6.41 (1H, s), 3.22 (3H, s), 3.08 (3H, s).

Example 44 4-N-methyl-6-[3-(morpholine-4-carbonyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(morpholine-4-carbonyl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 314; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.00-7.96 (1H, m), 7.92 (1H, s), 7.57 (1H, t, J=7.8 Hz), 7.52 (1H, dt, J=7.8 and 1.4 Hz), 6.27 (1H, s), 3.79-3.50 (8H, m), 2.94 (3H, s).

Example 45 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-(furan-2-ylmethyl)benzamide

Prepared according to general procedure 2 from {4-[(furan-2-ylmethyl)carbamoyl]phenyl}boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 324; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.93-7.90 (4H, m), 7.46-7.44 (1H, m), 6.39-6.37 (1H, m), 6.34-6.32 (1H, m), 6.28 (1H, s), 4.60 (2H, s), 2.94 (3H, s).

Example 46 N-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}methanesulfonamide

Prepared according to general procedure 2 from (4-methanesulfon-amidophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 294; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.72-7.70 (2H, m), 7.43-7.40 (2H, m), 6.29 (1H, s), 3.06 (3H, s), 3.03 (3H, s).

Example 47 N-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}acetamide

Prepared according to general procedure 2 from (4-acetamidophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.82-7.80 (2H, m), 7.75-7.73 (2H, m), 6.31 (1H, s), 3.03 (3H, s), 2.18 (3H, d, J=2.5 Hz).

Example 48 4-N-methyl-6-(pyridin-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (pyridin-4-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 202; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.79 (2H, dd, J=4.7 and 1.6 Hz), 7.76 (2H, d, J=4.7 Hz), 6.47 (1H, s), 3.07 (3H, s).

Example 49 6-(6-methoxypyridin-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (6-methoxypyridin-3-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 232; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.57 (1H, s), 8.03 (1H, d, J=7.3 Hz), 6.98 (1H, d, J=7.3 Hz), 6.30 (1H, s), 4.02 (3H, s), 3.07 (3H, s).

Example 50 6-(2-fluoro-4-phenylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2-fluoro-4-phenylphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 295; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.61 (5H, m), 7.54-7.44 (3H, m), 6.41 (1H, s), 6.30 (1H, s), 3.06 (3H, s).

Example 51 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzonitrile

Prepared according to general procedure 2 from (4-cyanophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 226; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.03 (2H, d, J=8.2 Hz), 7.84-7.80 (2H, m), 6.29 (1H, s), 2.93 (3H, s).

Example 52 4-N-methyl-6-(quinolin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (quinolin-5-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 252; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.98 (1H, dd, J=4.2 and 1.9 Hz), 8.49 (1H, d, J=8.6 Hz), 8.26 (1H, d, J=8.6 Hz), 7.95-7.91 (1H, m), 7.82 (1H, d, J=7.2 Hz), 7.67 (1H, dd, J=8.6 and 4.2 Hz), 6.23 (1H, s), 3.08 (3H, s).

Example 53 6-(4-chlorophenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronic acid and 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 261; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.73 (2H, m), 7.64-7.62 (2H, m), 6.36 (1H, s), 6.02-5.92 (1H, m), 5.33-5.31 (1H, m), 5.23-5.20 (1H, m), 4.18-4.16 (2H, m).

Example 54 6-(4-methoxyphenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronic acid and 6-chloro-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 257.

Example 55 6-(4-chlorophenyl)-4-N-cyclopentylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronic acid and 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 289; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.60 (2H, d, J=8.8 Hz), 7.51-7.49 (2H, m), 6.17 (1H, s), 4.36 (1H, s), 2.00-1.93 (2H, m), 1.73-1.65 (2H, m), 1.61-1.53 (2H, m), 1.50-1.43 (2H, m).

Example 56 4-N-cyclopentyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine and (4-methoxyphenyl)boronic acid. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.68 (2H, d, J=9.2 Hz), 7.12 (2H, d, J=9.2 Hz), 6.27 (1H, s), 4.47 (1H, q, J=6.7 Hz), 3.89 (3H, s), 2.10-2.03 (2H, m), 1.82-1.79 (2H, m), 1.72-1.63 (2H, m), 1.62-1.53 (2H, m).

Example 57 4-N-cyclopentyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(trifluoromethyl)-phenyl]boronic acid and 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.17 (1H, s), 8.08 (1H, d, J=7.9 Hz), 7.74 (1H, d, J=7.9 Hz), 7.65 (1H, t, J=7.9 Hz), 6.28 (1H, s), 4.29 (1H, s), 2.09-1.99 (2H, m), 1.75-1.74 (2H, m), 1.71-1.62 (2H, m), 1.60-1.49 (2H, m).

Example 58 6-(4-chlorophenyl)-4-N-cyclobutylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-chlorophenyl)boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 275; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 6.17 (1H, s), 4.42 (1H, s), 2.44-2.38 (2H, m), 2.02-1.94 (2H, m), 1.83-1.76 (2H, m).

Example 59 4-N-cyclobutyl-6-(4-methoxyphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxyphenyl)boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 271; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.68 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz), 6.22 (1H, s), 4.64 (1H, q, J=7.9 Hz), 3.90 (3H, s), 2.46-2.38 (2H, m), 2.12-2.01 (2H, m), 1.87-1.78 (2H, m).

Example 60 4-N-cyclobutyl-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from [3-(trifluoromethyl)phenyl]boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 309; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.68 (2H, d, J=8.5 Hz), 7.14 (2H, d, J=8.5 Hz), 6.22 (1H, s), 4.64 (1H, q, J=7.9 Hz), 3.90 (3H, s), 2.46-2.38 (2H, m), 2.12-2.01 (2H, m), 1.87-1.78 (2H, m).

Example 61 6-(2,3-dichlorophenyl)-4-N-pentylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from pentan-1-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.80-7.78 (1H, m), 7.52-7.50 (2H, m), 6.12 (1H, s), 3.54-3.50 (2H, m), 1.69-1.65 (2H, m), 1.42-1.39 (4H, m), 0.98-0.95 (3H, m).

Example 62 4-N-cyclopropyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 295; ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.51 (1H, dd, J=7.9 and 1.6 Hz), 7.41 (1H, dd, J=7.9 and 1.6 Hz), 7.28 (1H, t, J=7.9 Hz), 6.35 (1H, s), 5.21 (1H, s), 4.78 (2H, s), 2.63-2.47 (1H, m), 0.86-0.78 (2H, m), 0.64-0.57 (2H, m).

Example 63 4-N-tert-butyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from 2-methylpropan-2-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 311.

Example 64 4-N-cyclobutyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclobutanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 309; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.60-7.58 (1H, m), 7.37-7.34 (2H, m), 5.89 (1H, s), 4.46 (1H, s), 3.37 (2H, s), 2.43-2.35 (2H, m), 2.01-1.94 (2H, m), 1.80-1.72 (2H, m).

Example 65 4-N-cyclopentyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopentanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.62-7.56 (1H, m), 7.40-7.34 (2H, m), 5.93 (1H, s), 3.37 (1H, s), 2.09-1.98 (2H, m), 1.82-1.72 (2H, m), 1.71-1.61 (2H, m), 1.58-1.48 (2H, m).

Example 66 6-(2,3-dichlorophenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from ethanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.62-7.57 (1H, m), 7.40-7.35 (2H, m), 5.92 (1H, s), 3.44-3.36 (2H, m), 1.24 (3H, t, J=7.1 Hz).

Example 67 6-(2,3-dichlorophenyl)-4-N-(oxolan-3-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from oxolan-3-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.63-7.58 (1H, m), 7.39-7.35 (2H, m), 5.98 (1H, s), 4.59 (1H, s), 4.02-3.94 (2H, m), 3.90-3.82 (1H, m), 3.73-3.67 (1H, m), 2.36-2.26 (1H, m), 1.99-1.89 (1H, m).

Example 68 6-(3,4-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3,4-dichlorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.96 (1H, d, J=2.0 Hz), 7.77 (1H, d, J=8.5 Hz), 7.70-7.55 (2H, m), 6.35 (1H, s), 3.06 (3H, s).

Example 69 6-(4-tert-butylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (4-tert-butylphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.77 (2H, d, J=8.7 Hz), 7.53-7.48 (2H, m), 6.22 (1H, s), 2.93 (3H, s), 1.38 (9H, s).

Example 70 4-N-methyl-6-(4-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from (4-methylphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.73 (2H, d, J=8.9 Hz), 7.28 (2H, d, J=8.9 Hz), 6.20 (1H, s), 2.93 (3H, s), 2.41 (3H, s).

Example 71 6-(2,4-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2,4-dichlorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57 (1H, d, J=1.9 Hz), 7.48-7.41 (2H, m), 5.98 (1H, s), 2.92 (3H, s).

Example 72 4-N-methyl-6-(2,4,5-trifluorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2,4,5-trifluorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.86-7.75 (1H, m), 7.31-7.24 (1H, m), 6.25 (1H, s), 2.91 (3H, s).

Example 73 6-(4-fluoro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (4-fluoro-2-methoxyphenyl)-boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57 (1H, dd, J=8.5 and 6.3 Hz), 6.89 (1H, dd, J=11.4 and 2.5 Hz), 6.76 (1H, td, J=8.5 and 2.5 Hz), 6.19 (1H, s), 3.87 (3H, s), 2.90 (3H, s).

Example 74 6-(5-chloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (5-chloro-2-methylphenyl)-boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.33-7.23 (3H, m), 5.85 (1H, s), 2.92 (3H, s), 2.32 (3H, s).

Example 75 6-(2,4-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2,4-difluorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.88-7.79 (1H, m), 7.10-7.00 (2H, m), 6.19 (1H, d, J=2.0 Hz), 2.92 (3H, s).

Example 76 6-(5-fluoro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (5-fluoro-2-methoxyphenyl)-boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.36 (1H, dd, J=9.4 and 3.1 Hz), 7.15-7.04 (2H, m), 6.28 (1H, s), 3.85 (3H, s), 2.91 (3H, s).

Example 77 6-(2-chlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2-chlorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 235; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.51-7.44 (1H, m), 7.42-7.36 (2H, m), 5.98 (1H, s), 2.92 (3H, s).

Example 78 4-N-methyl-6-(pyridin-2-yl)pyrimidine-2,4-diamine

To a solution of 6-iodo-4-N-methylpyrimidine-2,4-diamine (1 eq.) and 2-(tributylstannyl)pyridine (1.3 eq.) in toluene (1 mL) were added CuI (0.25 eq.) and Pd(PPh₃)₄ (0.05 eq.). The reaction mixture was heated at 120° C. for 1 hour. The crude mixture was purified by HPLC. LCMS [M+H]⁺ 202.

Example 79 6-(4-methoxy-3-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-methoxy-3-methylphenyl)-boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.72-7.62 (2H, m), 6.99 (1H, d, J=8.3 Hz), 6.18 (1H, s), 3.91 (3H, s), 2.94 (3H, s), 2.28 (3H, s).

Example 80 6-(3-chloro-4-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-chloro-4-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.05-7.99 (1H, m), 7.87-7.79 (1H, m), 7.33 (1H, t, J=8.2 Hz), 6.23 (1H, s), 2.94 (3H, s).

Example 81 4-N-methyl-6-[4-(trifluoromethoxy)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from [4-(trifluoromethoxy)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.98-7.92 (2H, m), 7.38-7.32 (2H, m), 6.23 (1H, s), 2.93 (3H, s).

Example 82 6-(3-fluoro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-fluoro-4-methoxyphenyl)-boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.97-7.60 (2H, m), 7.21-7.12 (1H, m), 6.20 (1H, s), 3.95 (3H, s), 2.94 (3H, s).

Example 83 6-(3,4-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3,4-difluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.86-7.77 (1H, m), 7.74-7.66 (1H, m), 7.40-7.30 (1H, m), 6.23 (1H, s), 2.94 (3H, s).

Example 84 4-N-methyl-6-[4-(propan-2-yloxy)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from [4-(propan-2-yloxy)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259.

Example 85 6-[2-fluoro-3-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-fluoro-3-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.98 (1H, t, J=7.0 Hz), 7.87 (1H, t, J=7.0 Hz), 7.52 (1H, t, J=8.0 Hz), 6.27 (1H, d, J=1.5 Hz), 3.00 (3H, s).

Example 86 6-(2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,3-dimethylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.24-7.18 (1H, m), 7.17-7.05 (2H, m), 5.82 (1H, s), 2.92 (3H, s), 2.35 (3H, s), 2.22 (3H, s).

Example 87 6-(3-chloro-2-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-chloro-2-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.71-7.65 (1H, m), 7.58-7.53 (1H, m), 7.30-7.22 (1H, m), 6.18 (1H, d, J=2.1 Hz), 2.93 (3H, s).

Example 88 6-(4-chloro-3-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-chloro-3-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.73-7.65 (2H, m), 7.62-7.55 (1H, m), 6.34 (1H, s), 3.03 (3H, s).

Example 89 4-N-methyl-6-[2-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-(trifluoromethyl)-phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.80 (1H, d, J=8.1 Hz), 7.70 (1H, t, J=7.7 Hz), 7.61 (1H, t, J=7.7 Hz), 7.48 (1H, d, J=8.1 Hz), 5.88 (1H, s), 2.92 (3H, s).

Example 90 4-N-methyl-6-(1-methyl-1H-indazol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (1-methyl-1H-indazol-4-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.42 (1H, s), 7.69-7.63 (1H, m), 7.60-7.50 (2H, m), 6.33 (1H, s), 4.14 (3H, s), 2.97 (3H, s).

Example 91 6-[2-chloro-3-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-chloro-3-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 303; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.90-7.85 (1H, m), 7.71-7.66 (1H, m), 7.62-7.55 (1H, m), 5.95 (1H, s), 2.94 (3H, s).

Example 92 6-(2-chloro-3-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-chloro-3-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.46-7.38 (1H, m), 7.35-7.28 (2H, m), 5.98 (1H, s), 2.93 (3H, s).

Example 93 6-(2,3-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,3-difluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.58-7.51 (1H, m), 7.34-7.31 (1H, m), 7.29-7.22 (1H, m), 6.20 (1H, s), 2.93 (3H, s).

Example 94 6-(3-chloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-chloro-2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.47-7.41 (1H, m), 7.27-7.21 (2H, m), 5.85 (1H, s), 2.93 (3H, s), 2.36 (3H, s).

Example 95 6-(2,3-dichlorophenyl)-4-N,5-dimethylpyrimidine-2,4-diamine

Step 1: 4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine was prepared according to general procedure 2 from 4,6-dichloro-5-methylpyrimidin-2-amine and (2,3-dichlorophenyl)boronic acid (and using DMF instead of dioxane).

Step 2: 6-(2,3-dichlorophenyl)-4-N,5-dimethylpyrimidine-2,4-diamine was prepared according to general procedure 3 from methanamine and 4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine (prepared in step 1 above). LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.62 (1H, dd, J=7.9 and 1.9 Hz), 7.41 (1H, t, J=7.9 Hz), 7.27 (1H, dd, J=7.9 and 1.9 Hz), 3.01 (3H, s), 1.71 (3H, s).

Example 96 4-N-cyclopropyl-6-(2,3-dichlorophenyl)-5-methylpyrimidine-2,4-diamine

Was prepared according to general procedure 3 from cyclopropanamine and 4-chloro-6-(2,3-dichlorophenyl)-5-methylpyrimidin-2-amine (prepared in example 95, step 1 above). LCMS [M+H]⁺ 309; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83 (1H, dd, J=7.7 and 1.2 Hz), 7.56 (1H, t, J=7.8 Hz), 7.48 (1H, dd, J=7.8 and 1.2 Hz), 3.17-3.09 (1H, m), 1.79 (3H, s), 0.96-0.90 (2H, m), 0.82-0.75 (2H, m).

Example 97 6-(7-chloro-2H-1,3-benzodioxol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (7-chloro-2H-1,3-benzodioxol-5-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.11 (1H, s), 7.04 (1H, s), 6.13 (2H, s), 6.10 (1H, s), 3.04 (3H, s).

Example 98 6-(2,3-dichloro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Step 1: 4-chloro-6-(2,3-dichloro-5-methoxyphenyl)pyrimidin-2-amine was prepared according to general procedure 2 from 4,6-dichloropyrimidin-2-amine and 2,3-dichloro-4-methoxyphenyl)boronic acid.

Step 2: Prepared according to general procedure 3 from methanamine and 4-chloro-6-(2,3-dichloro-5-methoxyphenyl)pyrimidin-2-amine (prepared in step 1 above). LCMS [M+H]⁺ 299; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.49 (1H, d, J=8.6 Hz), 7.24 (1H, d, J=8.6 Hz), 6.11 (1H, s), 4.01 (3H, s), 3.09 (3H, s).

Example 99 6-(2,3-dichloro-5-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,3-dichloro-5-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 299; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.38 (1H, d, J=2.9 Hz), 7.12 (1H, d, J=2.9 Hz), 6.13 (1H, s), 3.88 (3H, s), 3.05 (3H, s).

Example 100 4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenol

Prepared according to general procedure 6 from (4-hydroxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 217; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.69 (2H, d, J=8.5 Hz), 6.85 (2H, d, J=8.5 Hz), 6.15 (1H, s), 4.59 (1H, s), 2.93 (3H, s).

Example 101 {3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}methanol

Prepared according to general procedure 6 from [3-(hydroxymethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83 (1H, s), 7.76-7.70 (1H, m), 7.45-7.41 (2H, m), 6.22 (1H, s), 4.68 (2H, s), 2.92 (3H, s).

Example 102 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzoic acid

Prepared according to general procedure 6 from 4-(dihydroxyboranyl)benzoic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245.

Example 103 Methyl 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzoate

Prepared according to general procedure 6 from [4-(methoxycarbonyl)-phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.12-8.06 (2H, m), 7.95 (2H, d, J=8.2 Hz), 6.28 (1H, s), 3.94 (3H, s), 2.93 (3H, s).

Example 104 6-[3-chloro-4-(morpholine-4-carbonyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [3-chloro-4-(morpholine-4-carbonyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 348; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.90 (1H, d, J=1.8 Hz), 7.75 (1H, dd, J=7.9 and 1.8 Hz), 7.59 (1H, d, J=7.9 Hz), 6.35 (1H, s), 3.85-3.74 (6H, m), 3.69-3.60 (2H, m), 3.04 (3H, s).

Example 105 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,3-dichlorophenol

Prepared according to general procedure 6 from 2,3-dichloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenol and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32 (1H, d, J=8.7 Hz), 7.04 (1H, d, J=8.7 Hz), 6.09 (1H, s), 3.04 (3H, s).

Example 106 Methyl (2E)-3-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoate

Prepared according to general procedure 6 from {4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.82 (4H, s), 7.76 (1H, d, J=16.0 Hz), 6.69 (1H, d, J=16.0 Hz), 6.36 (1H, s), 3.83 (3H, s), 3.04 (3H, s).

Example 107 Methyl (2E)-3-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoate

Prepared according to general procedure 6 from {3-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]phenyl}boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.99-7.95 (1H, m), 7.92-7.86 (1H, m), 7.83-7.73 (2H, m), 7.69-7.63 (1H, m), 6.72 (1H, d, J=16.0 Hz), 6.37 (1H, s), 3.83 (3H, s), 3.07 (3H, s).

Example 108 4-[2-amino-6-(methylamino)pyrimidin-4-yl]benzaldehyde

Prepared according to general procedure 6 from (4-formylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229.

Example 109 1-(4-(2-Amino-6-(methylamino)pyrimidin-4-yl)phenyl)ethanone

Prepared according to general procedure 6 from (4-acetylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.22-8.15 (2H, m), 7.88-7.82 (2H, m), 6.38 (1H, s), 3.05 (3H, s), 2.67 (3H, s).

Example 110 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-methylbenzamide

Prepared according to general procedure 6 from [4-(methylcarbamoyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 258; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.02 (2H, d, J=8.5 Hz), 7.83 (2H, d, J=8.5 Hz), 6.38 (1H, s), 3.06 (3H, s), 2.97 (3H, s).

Example 111 6-(4-ethenylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-ethenylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine.

LCMS [M+H]⁺ 227; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.63 (4H, m), 6.84 (1H, dd, J=17.5 and 10.7 Hz), 6.34 (1H, s), 5.98 (1H, d, J=17.5 Hz), 5.43 (1H, d, J=10.7 Hz), 3.06 (3H, s).

Example 112 6-(2,3-dimethylphenyl)-4-N-[2-(piperidin-1-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(piperidin-1-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 326.

Example 113 6-(2,3-dimethylphenyl)-4-N-[2-(morpholin-4-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(morpholin-4-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 328.

Example 114 4-N-cyclopropyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.42-7.31 (1H, m), 7.29-7.12 (2H, m), 6.44 (0.3H, s), 5.95 (0.7H, s), 3.13. (0.7H, s), 2.68 (0.3H, s), 2.36 (3H, s), 2.25 (3H, s), 0.95-0.79 (2H, m), 0.72-0.55 (2H, m).

Example 115 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-N-(4-methylphenyl)benzamide

Step 1: A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (48 mg, 0.30 mmol), 3-(dihydroxyboranyl)benzoic acid (60 mg, 0.36 mmol), K₂CO₃ (104 mg, 0.75 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (17 mg, 0.015 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. for 15 h. Concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 245.

Step 2: To a mixture of 3-(2-amino-6-(methylamino)pyrimidin-4-yl)benzoic acid (50 mg, 0.47 mmol) and p-toluidine (150 mg, 1.4 mmol) in DMF (2.5 mL) were added HATU (266 mg, 0.70 mmol) and NEt₃ (200 μL, 1.4 mmol). The mixture was stirred at rt overnight. The crude reaction mixture was purified by HPLC. LCMS [M+H]⁺ 334.

Example 116 6-(1H-indol-3-yl)-4-N-methylpyrimidine-2,4-diamine

To a solution of 4-N-methyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine (1 eq.; prepared in example 23) in MeOH (2 mL) was added 10% NaOH (1 mL). The reaction mixture was heated at 50° C. overnight and the crude product was purified by HPLC. LCMS [M+H]⁺ 240; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.04 (1H, d, J=7.7 Hz), 7.82 (1H, s), 7.46-7.36 (1H, m), 7.21-7.09 (2H, m), 6.29 (1H, s), 2.92 (3H, s).

Example 117 6-phenyl-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from phenylboronic acid and 6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 291; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.83-7.73 (2H, m), 7.47-7.37 (3H, m), 7.31-7.22 (4H, m), 7.21-7.15 (1H, m), 6.17 (1H, s), 3.60 (2H, t, J=7.3 Hz), 2.91 (2H, t, J=7.3 Hz).

Example 118 6-(2,3-dimethylphenyl)-4-N-(2-phenylethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-(2-phenylethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 319; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.31-7.23 (4H, m), 7.21-7.15 (2H, m), 7.10 (1H, t, J=7.0 Hz), 7.05 (1H, d, J=7.0 Hz), 5.77 (1H, s), 3.64-3.50 (2H, m), 2.90 (2H, t, J=7.6 Hz), 2.31 (3H, s), 2.19 (3H, s).

Example 119 6-(3-chlorophenyl)-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chlorophenyl)boronic acid and 6-chloro-4-N-(2,2-difluoroethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 285.

Example 120 6-(3-chloro-2-methoxypyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3-chloro-2-methoxypyridin-4-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 266.

Example 121 4-(2,3-dimethylphenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine (10 mg, 0.054 mmol, 1 eq.) in DMF/water (9:1) is added 2,3-dimethylphenylboronic acid (8.9 mg, 0.060 mmol, 1.1 eq.), Na₂CO₃ (11.5 mg, 0.11 mmol, 2 eq.) and Pd(PPh₃)₄ (3.1 mg, 0.002 mmol, 0.05 eq.). The mixture is heated at 120° C. in a microwave reactor until the reaction is complete as shown by LCMS. The crude mixture is then purified by HPLC to afford the desired product. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 12.05 (1H, br s), 8.88 (1H, br s), 7.37 (1H, d, J=6.9 Hz), 7.29 (1H, t, J=7.6 Hz), 7.17 (1H, d, J=6.3 Hz), 3.34-3.32 (2H, m), 2.32 (3H, s), 2.28-2.26 (2H, m), 2.09 (3H, s), 1.76-1.74 (2H, m).

Example 122 4-(2,3-dichlorophenyl)-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine (10 mg, 0.054 mmol, 1 eq.) in DMF/water (9:1) is added 2,3-dichlorophenylboronic acid (11.3 mg, 0.060 mmol, 1.1 eq.), Na₂CO₃ (11.5 mg, 0.11 mmol, 2 eq.) and Pd(PPh₃)₄ (3.1 mg, 0.002 mmol, 0.05 eq.). The mixture is heated at 120° C. in a microwave reactor until the reaction is complete as shown by LCMS. The crude mixture is then purified by HPLC to afford the desired product. LCMS [M+H]⁺ 295.

Example 123 4-[1-(benzenesulfonyl)-1H-indol-3-yl]-5H,6H,7H,8H-pyrido[2,3-d]pyrimidin-2-amine

To a solution of 4-chloro-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-2-amine (10 mg, 0.054 mmol, 1 eq.) in DMF/water (9:1) is added (1-(phenylsulfonyl)-1H-indol-3-yl)boronic acid (18.0 mg, 0.060 mmol, 1.1 eq.), Na₂CO₃ (11.5 mg, 0.11 mmol, 2 eq.) and Pd(PPh₃)₄ (3.1 mg, 0.002 mmol, 0.05 eq.). The mixture is heated at 120° C. in a microwave reactor until the reaction is complete as shown by LCMS. The crude mixture is then purified by HPLC to afford the desired product. LCMS [M+H]⁺ 406; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) 12.03 (1H, br s), 8.03 (1H, br s), 8.36 (1H, s), 8.09 (2H, dd, J=8.6 Hz and 1.2 Hz), 8.04 (1H, d, J=8.3 Hz), 7.78-7.76 (1H, m), 7.68-7.66 (2H, m), 7.61 (1H, d, J=7.8 Hz), 7.48 (1H, ddd, J=8.4 Hz, 7.3 Hz and 1.1 Hz), 7.38 (1H, ddd, J=8.0 Hz, 7.2 Hz and 1.0 Hz), 3.38-3.36 (2H, m), 2.48-2.46 (2H, m), 1.76-1.74 (2H, m).

Example 124 6-(3,5-difluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (3,5-difluorophenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 237.

Example 125 6-(2,3-dimethylphenyl)-4-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(4-methoxyphenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 349.

Example 126 6-(2,3-dimethylphenyl)-4-N-[2-(2-methoxyphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(2-methoxyphenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 349.

Example 127 6-(2,3-dimethylphenyl)-4-N-[2-(4-methylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(4-methylphenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 128 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(4-chlorophenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 353.

Example 129 6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-2-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(pyridin-2-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 320.

Example 130 6-(2,3-dimethylphenyl)-4-N-(2-phenylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-phenylpropan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 131 6-(2,3-dimethylphenyl)-4-N-(3-phenylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 3-phenylpropan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 333.

Example 132 6-(2,3-dimethylphenyl)-4-N-(2-phenoxyethyl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from (2-aminoethoxy)benzene and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 335.

Example 133 6-(2,3-dimethylphenyl)-4-N-[2-(phenylamino)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from N-(2-aminoethyl)aniline and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 334.

Example 134 6-(2,3-dimethylphenyl)-4-N-[2-(1H-indol-3-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 7 from 2-(1H-indol-3-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 358.

Example 135 6-(2,3-dimethylphenyl)-4-N-pentylpyrimidine-2,4-diamine

Prepared according to general procedure 7 from pentan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 285.

Example 136 1-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)imidazolidin-2-one

Prepared according to general procedure 7 from 1-(2-aminoethyl)imidazolidin-2-one and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 327.

Example 137 1-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 7 from 1-(3-aminopropyl)pyrrolidin-2-one and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340.

Example 138 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2,6-dimethylphenol

Prepared according to general procedure 6 from (4-hydroxy-3,5-dimethylphenyl)boronic acid. LCMS [M+H]⁺ 245; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.44 (2H, s), 6.12 (1H, s), 2.91 (3H, s), 2.27 (6H, s).

Example 139 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methoxyphenol

Prepared according to general procedure 6 from (4-hydroxy-3-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 247; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.46 (1H, s), 7.33 (1H, d, J=8.4 Hz), 6.86 (1H, d, J=8.0 Hz), 6.17 (1H, s), 3.34 (3H, s), 2.92 (3H, s).

Example 140 4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-fluorophenol

Prepared according to general procedure 6 from (3-fluoro-4-hydroxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 235.

Example 141 5-[2-amino-6-(methylamino)pyrimidin-4-yl]pyridin-2-ol

Prepared according to general procedure 6 from (6-hydroxypyridin-3-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 218; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.99 (1H, s), 7.86 (1H, d, J=9.6 Hz), 6.68 (1H, dd, J=9.6 and 0.4 Hz), 6.21 (1H, s), 3.04 (3H, s).

Example 142 {4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}methanol

Prepared according to general procedure 6 from [4-(hydroxymethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 231; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.79 (2H, d, J=8.0 Hz), 7.43 (2H, d, J=8.4 Hz), 6.21 (1H, s), 4.65 (2H, s), 2.91 (3H, s).

Example 143 4-N-methyl-6-(2-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.29-7.23 (4H, m), 5.83 (1H, s), 2.90 (3H, s), 2.33 (3H, s).

Example 144 6-[1-(4-chlorobenzenesulfonyl)-1H-indol-3-yl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-chlorobenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 414; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.15 (1H, s), 8.08 (1H, d, J=8.0 Hz), 8.04 (1H, d, J=8.0 Hz), 8.00-7.98 (2H, m), 7.57-7.55 (2H, m), 7.41 (1H, td, J=8.4 and 1.2 Hz), 7.35 (1H, td, J=8.0 and 0.8 Hz), 6.28 (1H, s), 2.29 (3H, s).

Example 145 4-N-methyl-6-(4-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-methyl-1H-indazol-5-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255.

Example 146 4-N-methyl-6-(6-methyl-1H-indazol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (6-methyl-1H-indazol-5-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.12 (1H, d, J=0.8 Hz), 7.88 (1H, s), 7.56 (1H, d, J=0.8 Hz), 6.09 (1H, s), 3.07 (3H, s), 2.50 (3H, d, J=0.8 Hz).

Example 147 4-N-methyl-6-(3-methylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-methylphenyl)boronic acid. LCMS [M+H]⁺ 215; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56 (1H, s), 7.51-7.47 (3H, m), 6.32 (1H, s), 3.06 (3H, s), 2.47 (3H, s).

Example 148 6-(1H-indol-5-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (1H-indol-5-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.00 (1H, dd, J=1.6 and 0.4 Hz), 7.59 (1H, td, J=8.4 and 0.8 Hz), 7.47 (1H, dd, J=8.4 and 1.6 Hz), 7.42 (1H, d, J=3.2 Hz), 6.63 (1H, dd, J=3.2 and 1.2 Hz), 6.35 (1H, s), 3.06 (3H, s).

Example 149 6-(3-chloropyridin-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (3-chloropyridin-4-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 236; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.83 (1H, s), 8.71 (1H, d, J=5.2 Hz), 7.62 (1H, d, J=4.8 Hz), 6.24 (1H, s), 3.07 (3H, s).

Example 150 {5-[2-amino-6-(methylamino)pyrimidin-4-yl]pyridin-2-yl}methanol

Prepared according to general procedure 6 from [6-(hydroxymethyl)pyridin-3-yl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 232.

Example 151 4-N-cyclobutyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.20 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.2 Hz), 7.08 (1H, d, J=7.2 Hz), 5.77 (1H, s), 4.44 (1H, br s), 2.44-2.36 (2H, m), 2.34 (3H, s), 2.21 (3H, s), 2.04-1.94 (m, 2H), 1.82-1.73 (m, 2H).

Example 152 4-N-cyclobutyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 434; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.39 (1H, s), 8.09 (1H, d, J=8.4 Hz), 7.96-7.94 (2H, m), 7.84 (1H, d, J=8.0 Hz), 7.50 (1H, td, J=7.2 and 0.8 Hz), 7.35 (1H, td, J=7.2 and 0.8 Hz), 7.41-7.39 (2H, m), 6.44 (1H, s), 4.66 (1H, quintet, J=8.4 Hz), 2.47-2.41 (2H, m), 2.39 (3H, s), 2.14-2.04 (2H, m), 1.89-1.82 (2H, m).

Example 153 4-N-cyclopentyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.6 Hz), 7.08 (1H, dd, J=7.6 and 1.6 Hz), 5.81 (1H, s), 4.25 (1H, br s), 2.33 (3H, s), 2.22 (3H, s), 2.06-2.00 (2H, m), 1.81-1.74 (2H, m), 1.71-1.63 (2H, m), 1.58-1.51 (2H, m).

Example 154 4-N-cyclopentyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-cyclopentylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.38 (1H, s), 8.10 (1H, d, J=8.4 Hz), 7.96-7.94 (2H, m), 7.84 (1H, d, J=8.0 Hz), 7.50 (1H, td, J=7.2 and 1.2 Hz), 7.42 (1H, td, J=7.2 and 0.8 Hz), 7.41-7.39 (2H, m), 6.48 (1H, s), 4.51 (1H, quintet, J=6.8 Hz), 2.39 (3H, s), 2.14-2.05 (2H, m), 1.84-1.78 (2H, m), 1.75-1.66 (2H, m), 1.63-1.57 (2H, m).

Example 155 4-N-methyl-6-{1-[4-(trifluoromethyl)benzenesulfonyl]-1H-indol-3-yl}pyrimidine-2,4-diamine

Prepared according to general procedure 8 from {1-[4-(trifluoromethyl)benzenesulfonyl]-1H-indol-3-yl}boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.19 (2H, d, J=8.4 Hz), 8.16 (1H, s), 8.08-8.04 (2H, m), 7.84 (2H, d, J=8.4 Hz), 7.41 (1H, td, J=7.6 and 0.8 Hz), 7.34 (1H, td, J=8.0 and 0.8 Hz), 6.26 (1H, s), 2.92 (s, 3H).

Example 156 4-N-cyclohexyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 297; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.12 (1H, t, J=7.6 Hz), 7.08 (1H, dd, J=7.6 and 1.6 Hz), 5.78 (1H, s), 3.82 (1H, br s), 2.33 (3H, s), 2.21 (3H, s), 2.03-1.99 (2H, m), 1.83-1.78 (2H, m), 1.71-1.66 (1H, m), 1.48-1.37 (2H, m), 1.31-1.21 (3H, m).

Example 157 4-N-cyclohexyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-cyclohexylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 462; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.08 (1H, d, J=8.0 Hz), 7.95-7.93 (2H, m), 7.83 (1H, d, J=8.0 Hz), 7.48 (1H, td, J=7.2 and 0.8 Hz), 7.41 (1H, td, J=8.0 and 1.2 Hz), 7.40-7.38 (2H, m), 6.46 (1H, s), 4.11-4.05 (1H, m), 2.38 (3H, s), 2.04-2.00 (2H, m), 1.86-1.82 (2H, m), 1.72-1.68 (1H, m), 1.48-1.26 (5H, m).

Example 158 6-(2,3-dimethylphenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.13 (1H, t, J=7.6 Hz), 7.08 (1H, dd, J=7.6 and 1.2 Hz), 5.80 (1H, s), 3.41-3.36 (2H, m), 2.33 (3H, s), 2.21 (3H, s), 1.23 (3H, t, J=7.2 Hz).

Example 159 4-N-ethyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 408; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.12 (1H, s), 8.05-8.01 (2H, m), 7.87-7.85 (2H, m), 7.37 (1H, td, J=7.2 and 1.2 Hz), 7.34-7.32 (2H, m), 7.30 (1H, td, J=8.0 and 1.2 Hz), 6.26 (1H, s), 3.39 (2H, q, J=7.2 Hz), 2.34 (3H, s), 1.24 (3H, t, J=7.2 Hz).

Example 160 4-N-tert-butyl-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 271; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=7.2 Hz), 7.12 (1H, t, J=7.6 Hz), 7.07 (1H, dd, J=7.6 and 1.6 Hz), 5.81 (1H, s), 2.33 (3H, s), 2.21 (3H, s), 1.49 (9H, s).

Example 161 4-N-tert-butyl-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 4-N-tert-butyl-6-chloropyrimidine-2,4-diamine. LCMS [M+H]⁺ 436; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.36 (1H, s), 8.08 (1H, d, J=8.4 Hz), 7.95-7.93 (2H, m), 7.84 (1H, d, J=7.6 Hz), 7.48 (1H, td, J=7.2 and 1.2 Hz), 7.40 (1H, td, J=8.4 and 1.2 Hz), 7.40-7.38 (2H, m), 6.52 (1H, s), 2.38 (3H, s), 1.54 (9H, s).

Example 162 6-(2,3-dimethylphenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.36 (1H, d, J=7.2 Hz), 7.25 (1H, t, J=7.6 Hz), 7.19 (1H, d, J=7.2 Hz), 5.96 (1H, s), 4.39 (1H, septet, J=6.4 Hz), 2.37 (3H, s), 2.26 (3H, s), 1.29 (3H, s), 1.27 (3H, s).

Example 163 6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-(propan-2-yl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 422; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.12 (1H, s), 8.05-8.02 (2H, m), 7.89-7.86 (2H, m), 7.40-7.30 (4H, m), 6.25 (1H, s), 4.19 (1H, br s), 2.36 (3H, s), 1.26 (3H, s), 1.24 (3H, s).

Example 164 4-N-(cyclopropylmethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 269.

Example 165 4-N-(cyclopropylmethyl)-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-(cyclopropylmethyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 434; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.06-8.02 (2H, m), 7.88-7.86 (2H, m), 7.40-7.30 (5H, m), 6.31 (1H, s), 3.25 (2H, d, J=6.8 Hz), 1.14-1.11 (1H, m), 0.57-0.55 (2H, m), 0.30-0.28 (2H, m).

Example 166 4-N-[(1R)-1-cyclopropylethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=6.8 Hz), 7.13 (1H, t, J=7.6 Hz), 7.09 (1H, dd, J=7.6 and 1.2 Hz), 5.80 (1H, s), 3.58 (1H, br s), 2.34 (3H, s), 2.22 (3H, s), 1.28 (3H, d, J=6.4 Hz), 0.99-0.92 (1H, m), 0.57-0.45 (2H, m), 0.44-0.38 (1H, m), 0.29-0.23 (1H, m).

Example 167 4-N-[(1R)-1-cyclopropylethyl]-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-[(1R)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.37 (1H, s), 8.08 (1H, d, J=8.0 Hz), 7.95-7.93 (2H, m), 7.84 (1H, d, J=7.6 Hz), 7.49 (1H, dt, J=7.6 and 1.2 Hz), 7.42 (1H, dt, J=8.0 and 0.8 Hz), 7.40-7.38 (2H, m), 6.47 (1H, s), 3.78-3.71 (1H, m), 2.38 (3H, s), 1.33 (3H, d, J=6.8 Hz), 1.04-0.99 (1H, m), 0.64-0.57 (1H, m), 0.56-0.49 (1H, m), 0.47-0.41 (1H, m), 0.33-0.27 (1H, m).

Example 168 4-N-[(1S)-1-cyclopropylethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=6.8 Hz), 7.11 (1H, t, J=7.6 Hz), 7.07 (1H, dd, J=7.6 and 1.6 Hz), 5.78 (1H, s), 3.56 (1H, br s), 2.32 (3H, s), 2.20 (3H, s), 1.27 (3H, d, J=6.4 Hz), 0.98-0.91 (1H, m), 0.56-0.43 (2H, m), 0.42-0.36 (1H, m), 0.27-0.21 (1H, m).

Example 169 4-N-[(1S)-1-cyclopropylethyl]-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-[(1S)-1-cyclopropylethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 448; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.37 (1H, s), 8.09 (1H, d, J=8.4 Hz), 7.96-7.94 (2H, m), 7.85 (1H, d, J=8.0 Hz), 7.49 (1H, dt, J=7.6 and 1.2 Hz), 7.42 (1H, dt, J=8.0 and 1.2 Hz), 7.41-7.39 (2H, m), 6.47 (1H, s), 3.78-3.71 (1H, m), 2.39 (3H, s), 1.33 (3H, d, J=6.8 Hz), 1.05-0.98 (1H, m), 0.63-0.58 (1H, m), 0.57-0.50 (1H, m), 0.48-0.42 (1H, m), 0.33-0.27 (1H, m).

Example 170 6-(1-benzofuran-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (1-benzofuran-3-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 241; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.27 (1H, s), 8.07 (1H, dd, J=8.0 and 1.2 Hz), 7.58-7.56 (1H, m), 7.35 (2H, dt, J=7.6 and 1.2 Hz), 6.32 (1H, s), 2.95 (3H, s).

Example 171 6-(2-chloro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2-chloro-5-methylphenyl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.35 (1H, d, J=8.0 Hz), 7.28 (1H, d, J=2.0 Hz), 7.23-7.20 (1H, m), 5.97 (1H, s), 2.92 (3H, s), 2.38 (3H, s).

Example 172 6-(1-benzothiophen-3-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (1-benzothiophen-3-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 257; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.27 (1H, d, J=7.2 Hz), 7.97-7.94 (1H, m), 7.92 (1H, s), 7.45 (1H, dt, J=7.2 and 1.6 Hz), 7.41 (1H, dt, J=7.2 and 1.6 Hz), 6.20 (1H, s), 2.95 (3H, s).

Example 173 2-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}propan-2-ol

Prepared according to general procedure 2 from [4-(2-hydroxypropan-2-yl)phenyl]boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.82-7.80 (2H, m), 7.60-7.57 (2H, m), 6.23 (1H, s), 2.94 (3H, s), 1.58 (6H, s).

Example 174 6-(1H-indol-4-yl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (1H-indol-4-yl)boronic acid and 6-chloro-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.50-7.48 (1H, m), 7.38 (1H, dd, J=7.6 and 0.8 Hz), 7.34 (1H, d, J=3.2 Hz), 7.21 (1H, t, J=7.6 Hz), 6.80 (1H, dd, J=3.2 and 0.8 Hz), 6.31 (1H, s), 2.96 (3H, s).

Example 175 4-N-cyclohexyl-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclohexanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.63-7.61 (1H, m), 7.40 (1H, d, J=2.0 Hz), 7.39 (1H, s), 5.93 (1H, s), 3.88 (1H, br s), 2.06-2.02 (2H, m), 1.86-1.81 (2H, m), 1.73-1.69 (1H, m), 1.50-1.40 (2H, m), 1.34-1.25 (3H, m).

Example 176 6-(2,3-dichlorophenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from propan-2-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 297; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz), 7.37 (1H, s), 5.92 (1H, s), 4.17 (1H, br s), 1.25 (3H, s), 1.24 (3H, s).

Example 177 4-N-(cyclopropylmethyl)-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropylmethanamine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 309.

Example 178 4-N-[(1S)-1-cyclopropylethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from (1S)-1-cyclopropylethan-1-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz), 7.37 (1H, s), 5.92 (1H, s), 3.59 (1H, br s), 1.28 (3H, d, J=6.8 Hz), 0.99-0.92 (2H, m), 0.53-0.48 (2H, m), 0.46-0.38 (1H, m), 0.29-0.23 (1H, m).

Example 179 4-N-[(1R)-1-cyclopropylethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from (1R)-1-cyclopropylethan-1-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.61-7.59 (1H, m), 7.38 (1H, d, J=2.0 Hz), 7.37 (1H, s), 5.92 (1H, s), 3.59 (1H, br s), 1.28 (3H, d, J=6.8 Hz), 0.99-0.92 (2H, m), 0.58-0.47 (2H, m), 0.46-0.38 (1H, m), 0.29-0.23 (1H, m).

Example 180 6-(2,3-dichlorophenyl)-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from 2,2-dimethylpropan-1-amine and 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 325; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.61-7.58 (1H, m), 7.38 (1H, d, J=2.0 Hz), 7.36 (1H, s), 6.01 (1H, s), 3.27 (2H, br s), 0.98 (9H, s).

Example 181 6-(2,3-dimethylphenyl)-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine

Prepared according to general procedure 5 from (2,3-dimethylphenyl)boronic acid and 6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 285; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.20 (1H, d, J=6.8 Hz), 7.14 (1H, t, J=7.6 Hz), 7.10 (1H, dd, J=7.6 and 1.6 Hz), 5.90 (1H, s), 2.34 (3H, s), 2.22 (3H, s), 1.00 (9H, s).

Example 182 4-N-(2,2-dimethylpropyl)-6-[1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 8 from [1-(4-methylbenzenesulfonyl)-1H-indol-3-yl]boronic acid and 6-chloro-4-N-(2,2-dimethylpropyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 450; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.14 (1H, s), 8.08 (1H, d, J=7.6), 8.04 (1H, dt, J=8.0 and 1.2 Hz), 7.90-7.88 (2H, m), 7.39 (1H, td, J=7.2 and 1.2 Hz), 7.37-7.34 (2H, m), 7.33 (1H, td, J=7.2 and 1.2 Hz), 6.38 (1H, s), 3.27 (2H, s), 2.37 (3H, s), 1.02 (9H, s).

Example 183 6-(5-bromo-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-bromo-2-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 310; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.72 (1H, d, J=2.4 Hz), 7.52 (1H, dd, J=8.8 and 2.8 Hz), 7.04 (1H, d, J=9.2 Hz), 6.25 (1H, s), 3.87 (3H, s), 2.91 (s, 3H).

Example 184 6-(2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,5-dimethylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 229; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.16-7.13 (2H, m), 7.11 (1H, s), 5.84 (1H, s), 2.92 (3H, s), 2.35 (3H, s), 2.29 (3H, s).

Example 185 4-N-methyl-6-[2-(trifluoromethyl)pyridin-3-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-(trifluoromethyl)pyridin-3-yl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 270.

Example 186 4-N-methyl-6-(pyrimidin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (pyrimidin-5-yl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 203.

Example 187 6-[4-(benzyloxy)-2-methylphenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [4-(benzyloxy)-2-methylphenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 321; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.47-7.46 (2H, m), 7.41-7.38 (2H, m), 7.35-7.32 (1H, m), 7.24 (1H, d, J=8.4 Hz), 6.92-6.87 (2H, m), 5.84 (1H, s), 5.14 (2H, s), 2.91 (3H, s), 2.34 (3H, s).

Example 188 6-(4-methoxy-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-methoxy-2,5-dimethylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 259; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.08 (1H, s), 6.79 (1H, s), 5.83 (1H, s), 3.86 (3H, s), 2.91 (3H, s), 2.34 (3H, s), 2.19 (3H, s).

Example 189 4-N-methyl-6-(2,4,5-trimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,4,5-trimethylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 243; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.07 (1H, s), 7.03 (1H, s), 5.83 (1H, s), 2.91 (3H, s), 2.28 (9H, s).

Example 190 2-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-chlorobenzonitrile

Prepared according to general procedure 6 from (5-chloro-2-cyanophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 260.

Example 191 6-(4,5-dichloro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4,5-dichloro-2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.62 (1H, s), 7.61 (1H, s), 6.06 (1H, s), 3.04 (3H, s), 2.36 (3H, s).

Example 192 6-(2,5-dichloro-4-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,5-dichloro-4-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 299; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.52 (1H, s), 7.22 (1H, s), 6.03 (1H, s), 3.96 (3H, s), 2.92 (3H, s).

Example 193 6-(4-fluoro-2,5-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (4-fluoro-2,5-dimethylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 247; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.16 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=10.8 Hz), 5.83 (1H, s), 2.91 (3H, s), 2.30 (3H, s), 2.27 (3H, s).

Example 194 4-N-methyl-6-[2-methyl-5-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-methyl-5-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 283; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.78-7.73 (2H, m), 7.61 (1H, d, J=8.0 Hz), 6.08 (1H, s), 3.05 (3H, s), 2.46 (3H, s).

Example 195 6-[5-chloro-2-methyl-4-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [5-chloro-2-methyl-4-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 317; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.69 (1H, s), 7.53 (1H, s), 5.89 (1H, s), 2.93 (3H, s), 2.40 (3H, s).

Example 196 6-[2,5-bis(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2,5-bis(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.20-8.15 (2H, m), 8.10 (1H, s), 6.15 (1H, s), 3.08 (3H, s).

Example 197 6-(5-tert-butyl-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-tert-butyl-2-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.64 (1H, dd, J=8.8 and 2.4 Hz), 7.51 (1H, s), 7.17 (1H, d, J=8.8 Hz), 6.25 (1H, s), 3.94 (3H, s), 3.05 (3H, s), 1.37 (9H, s).

Example 198 6-[2-methoxy-5-(propan-2-yl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-methoxy-5-(propan-2-yl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.49 (1H, dd, J=8.4 and 2.0 Hz), 7.39 (1H, s), 7.17 (1H, d, J=8.8 Hz), 6.28 (1H, s), 3.95 (3H, s), 3.06 (3H, s), 2.98 (1H, sept, J=6.8 Hz), 1.31 (3H, s), 1.30 (3H, s).

Example 199 6-[2-chloro-5-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [2-chloro-5-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 303; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.87 (1H, br s), 7.82 (1H, d, J=2.0 Hz), 7.81 (1H, s), 6.14 (1H, s), 3.03 (3H, s).

Example 200 6-(2-fluoro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-fluoro-5-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 233; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.58 (1H, dd, J=7.2 and 2.0 Hz), 7.28-7.25 (1H, m), 7.10-7.06 (1H, m), 6.02 (1H, d, J=1.6 Hz), 2.94 (3H, s), 2.40 (3H, s).

Example 201 6-(5-chloro-2-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-chloro-2-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 265; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.58-7.57 (1H, m), 7.56 (1H, d, J=2.8 Hz), 7.23 (1H, d, J=9.6 Hz), 6.27 (1H, s), 3.96 (3H, s), 3.05 (3H, s).

Example 202 6-(5-fluoro-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-fluoro-2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 233; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.31-7.27 (1H, m), 7.08-7.04 (2H, m), 5.87 (1H, s), 2.94 (3H, s), 2.33 (3H, s).

Example 203 6-(2,5-dimethoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,5-dimethoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 261; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.18 (1H, d, J=3.2 Hz), 7.04 (1H, d, J=9.2 Hz), 6.98 (1H, dd, J=8.8 and 3.2 Hz), 6.27 (1H, s), 3.83 (6H, s), 2.93 (3H, s).

Example 204 6-(2-methoxy-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-methoxy-5-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 245; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.36 (1H, s), 7.20 (1H, d, J=8.8 Hz), 6.98 (1H, d, J=8.8 Hz), 6.20 (1H, s), 3.83 (3H, s), 2.91 (3H, s), 2.33 (3H, s).

Example 205 6-(2-chloro-5-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-chloro-5-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.54-7.50 (1H, m), 7.25 (1H, dd, J=9.2 and 3.2 Hz), 7.19 (1H, td, J=8.8 and 3.2 Hz), 6.01 (1H, s), 2.93 (3H, s).

Example 206 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-fluorobenzonitrile

Prepared according to general procedure 6 from (5-cyano-2-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 244; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.26 (1H, dd, J=6.8 and 2.0 Hz), 7.87-7.84 (1H, m), 7.45-7.40 (1H, m), 6.27 (1H, d, J=2.0 Hz), 2.93 (3H, s).

Example 207 6-(2-chloro-5-methoxyphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-chloro-5-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 265; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.39 (1H, d, J=8.8 Hz), 7.02 (1H, d, J=3.2 Hz), 6.98 (1H, dd, J=8.8 and 3.2 Hz), 5.99 (1H, s), 3.84 (3H, s), 2.92 (3H, s).

Example 208 6-[5-fluoro-2-(trifluoromethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from [5-fluoro-2-(trifluoromethyl)phenyl]boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 287; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.87-7.83 (1H, m), 7.39-7.34 (1H, m), 7.25 (1H, dd, J=9.2 and 2.8 Hz), 5.89 (1H, s), 2.92 (3H, s).

Example 209 6-(2,5-dichlorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2,5-dichlorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 269; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.51-7.49 (2H, m), 7.42 (1H, dd, J=8.4 and 2.4 Hz), 6.01 (1H, s), 2.92 (3H, s).

Example 210 6-(5-chloro-2-fluorophenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-chloro-2-fluorophenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 253; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.75-7.23 (1H, m), 7.69-7.65 (1H, m), 7.40 (1H, m), 6.31 (1H, s), 3.07 (3H, s).

Example 211 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-methylbenzonitrile

Prepared according to general procedure 6 from (5-cyano-2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 240; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.68-7.66 (2H, m), 7.48 (1H, d, J=7.6 Hz), 5.88 (1H, s), 2.93 (3H, s), 2.44 (3H, s).

Example 212 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-4-methoxybenzonitrile

Prepared according to general procedure 6 from (5-cyano-2-methoxyphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 256; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.95 (1H, d, J=2.4 Hz), 7.98 (1H, dd, J=8.8 and 2.0 Hz), 7.27 (1H, d, J=8.8 Hz), 6.26 (1H, s), 3.97 (3H, s), 2.92 (3H, s).

Example 213 6-(2-chloro-5-fluoro-4-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-chloro-5-fluoro-4-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 267; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.39 (1H, d, J=6.8 Hz), 7.19 (1H, d, J=9.6 Hz), 6.02 (1H, s), 2.92 (3H, s), 2.32 (3H, d, J=1.6 Hz).

Example 214 6-(5-chloro-2-fluoro-4-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-chloro-2-fluoro-4-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 267; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.72 (1H, d, J=6.8 Hz), 7.19 (1H, d, J=11.2 Hz), 6.31 (1H, s), 3.05 (3H, s), 2.48 (3H, s).

Example 215 6-(2-chloro-4-fluoro-5-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (2-chloro-4-fluoro-5-methylphenyl)boronic acid. and 6-iodo-4-N-methylpyrimidine-2,4-diamine LCMS [M+H]⁺ 267; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.36 (1H, d, J=8.4 Hz), 7.23 (1H, d, J=9.6 Hz), 5.96 (1H, s), 2.91 (3H, s), 2.29 (3H, d, J=1.6 Hz).

Example 216 4-N-cyclopropyl-6-(4-fluoro-2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-fluoro-2,5-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=8.0 Hz), 6.97 (1H, d, J=10.4 Hz), 6.03 (1H, s), 2.63 (1H, br s), 2.33 (3H, s), 2.28 (3H, s), 0.84-0.79 (2H, m), 0.60-0.56 (2H, m).

Example 217 4-N-cyclopropyl-6-(4-methoxy-2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-methoxy-2,5-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 285.

Example 218 4-N-cyclopropyl-6-(2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,5-dimethylphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.30-7.28 (2H, m), 7.23 (1H, s), 6.00 (1H, s), 3.06 (1H, br s), 2.40 (3H, s), 2.36 (3H, s), 0.93-0.88 (2H, m), 0.69-0.66 (2H, m).

Example 219 6-(5-chloro-2-methylphenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (5-chloro-2-methylphenyl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 275; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.33-7.27 (3H, m), 6.05 (1H, s), 2.65 (1H, br s), 0.84-0.79 (2H, m), 0.60-0.56 (2H, m).

Example 220 6-(5-chloro-2-methylphenyl)-4-N-cyclobutylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (5-chloro-2-methylphenyl)boronic acid and 6-chloro-4-N-cyclobutylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 289; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.33-7.26 (3H, m), 5.81 (1H, s), 4.45 (1H, br s), 2.44-2.37 (2H, m), 2.32 (3H, s), 2.05-1.95 (2H, m), 1.83-1.74 (2H, m).

Example 221 6-(5-chloro-2-methylphenyl)-4-N-ethylpyrimidine-2,4-diamine

Prepared according to general procedure 2 from (5-chloro-2-methylphenyl)boronic acid and 6-chloro-4-N-ethylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 263; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.51-7.46 (2H, m), 7.41 (1H, d, J=8.4 Hz), 6.05 (1H, s), 3.57 (2H, q, J=6.8 Hz), 2.37 (3H, s), 1.28 (3H, t, J=7.2 Hz).

Example 222 6-(5-chloro-2-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (5-chloro-2-methylphenyl)boronic acid and 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 374; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (7H, m), 5.81 (1H, s), 3.64-3.60 (2H, m), 2.92 (2H, t, J=7.6 Hz), 2.31 (3H, s).

Example 223 4-N-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (4-fluoro-2,5-dimethylphenyl)boronic acid and 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 371; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (4H, m), 7.14 (1H, d, J=8.0 Hz), 6.94 (1H, d, J=10.8 Hz), 5.79 (1H, s), 3.63-3.59 (2H, m), 2.92 (2H, t, J=7.2 Hz), 2.30 (3H, s), 2.27 (3H, s).

Example 224 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,5-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (2,5-dimethylphenyl)boronic acid and 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine. LCMS [M+H]⁺ 353; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.32-7.26 (4H, m), 7.16-7.09 (3H, m), 5.80 (1H, s), 3.61 (2H, t, J=6.4 Hz), 2.92 (2H, t, J=7.2 Hz), 2.35 (3H, s), 2.28 (3H, s).

Example 225 1-(3-{[2-amino-6-(quinolin-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 2 from (quinolin-5-yl)boronic acid and 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one. LCMS [M+H]⁺ 363; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.90 (1H, dd, J=4.0 and 1.6 Hz), 8.64 (1H, d, J=8.8 Hz), 8.12 (1H, d, J=8.4 Hz), 7.88-7.84 (1H, m), 7.71 (1H, d, J=7.2 Hz), 7.59-7.56 (1H, m), 6.07 (1H, s), 3.53 (2H, t, J=6.8 Hz), 3.42 (4H, t, J=6.8 Hz), 2.42 (2H, t, J=8.0 Hz), 2.12-2.05 (2H, m), 1.93-1.86 (2H, m).

Example 226 6-(2-chloro-3-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from methanamine and 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 249; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56-7.54 (1H, m), 7.42-7.37 (2H, m), 6.11 (1H, s), 3.05 (3H, s), 2.49 (3H, s).

Example 227 6-(2-chloro-3-methylphenyl)-4-N-cyclopropylpyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 275; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.56 (1H, d, J=5.6 Hz), 7.42-7.39 (2H, m), 6.07 (1H, s), 3.09 (1H, br s), 2.50 (3H, s), 0.92-0.90 (2H, m), 0.68 (2H, br s).

Example 228 6-(2-chloro-3-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 3 from 2-(4-chlorophenyl)ethan-1-amine and 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 373; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57-7.55 (1H, m), 7.41 (1H, t, J=7.6 Hz), 7.37 (1H, dd, J=8.0 and 2.0 Hz), 7.34-7.28 (4H, m), 6.08 (1H, s), 3.79 (2H, t, J=7.2 Hz), 2.97 (2H, t, J=7.2 Hz), 2.49 (3H, s).

Example 229 1-(3-{[2-amino-6-(2-chloro-3-methylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 3 from 1-(3-aminopropyl)pyrrolidin-2-one and 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 360; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.57-7.55 (1H, m), 7.44-7.38 (2H, m), 6.13 (1H, s),3.55 (2H, t, J=5.6 Hz), 3.52 (2H, t, J=7.2 Hz), 3.41 (2H, t, J=6.8 Hz), 2.49 (3H, s), 2.42 (2H, t, J=8.0 Hz), 2.09 (2H, quintet, J=7.6 Hz), 1.92 (2H, quintet, J=7.2 Hz).

Example 230 4-N-cyclopropyl-6-(1H-indol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and 4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 266; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.67 (1H, d, J=7.6 Hz), 7.50 (1H, s), 7.33 (2H, d, J=7.2 Hz), 6.71 (1H, s), 6.43 (1H, s), 3.10 (1H, br s), 0.92 (2H, br s), 0.69 (2H, br s).

Example 231 4-N-[2-(4-chlorophenyl)ethyl]-6-(1H-indol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from 2-(4-chlorophenyl)ethan-1-amine and 4-chloro-6-(1H-indol-4-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 364; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.67-7.66 (1H, m), 7.52-7.46 (1H, m), 7.35-7.29 (6H, m), 6.86 (1H, s), 6.44 (1H, s), 3.80 (2H, t, J=7.2 Hz), 2.95 (2H, t, J=6.8 Hz).

Example 232 4-N-cyclopropyl-6-(quinolin-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 3 from cyclopropanamine and 4-chloro-6-(quinolin-5-yl)pyrimidin-2-amine. LCMS [M+H]⁺ 278; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.91 (1H, dd, J=4 and 1.6 Hz), 8.66 (1H, d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz), 7.89-7.85 (1H, m), 7.74 (1H, d, J=6.8 Hz), 7.59-7.56 (1H, m), 6.26 (1H, s), 2.69 (1H, br s), 0.85-0.80 (2H, m), 0.62-0.59 (2H, m).

Example 233 (2E)-3-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enoic acid

Prepared according to general procedure 6 from (2E)-3-[4-(dihydroxyboranyl)phenyl]prop-2-enoic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 271.

Example 234 Tert-butyl 3-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-azetidine-1-carboxylate

Prepared according to general procedure 3 from tert-butyl 3-(aminomethyl)azetidine-1-carboxylate and 4-chloro-6-(2,3-dimethylphenyl)-pyrimidin-2-amine. LCMS [M+H]⁺ 384; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.6 Hz), 7.12 (1H, t, J=7.6 Hz), 7.07 (1H, d, J=7.6 Hz), 5.82 (s, 1H), 4.05-4.00 (2H, m), 3.73-3.69 (2H, m), 3.60-3.59 (2H, m), 2.92-2.82 (1H, m), 2.33 (3H, s), 2.21 (3H, s), 1.45 (9H, s).

Example 235 4-N-cyclopropyl-6-(1H-indol-5-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from (1H-indol-5-yl)boronic acid and 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 266.

Example 236 1-(3-{[2-amino-6-(1H-indol-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

Prepared according to general procedure 2 from (2,3-dimethylphenyl)boronic acid and 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one. LCMS [M+H]⁺ 351; ¹H NMR (400 MHz, CD₃OD) δ_(H) 8.02 (1H, d, J=1.6 Hz), 7.59 (1H, d, J=8.4 Hz), 7.48 (1H, dd, J=8.4 and 2.0 Hz), 7.42 (1H, d, J=3.2 Hz), 6.64 (1H, d, J=3.2 Hz), 6.37 (1H, s), 3.57-3.51 (4H, m), 3.42 (2H, t, J=7.2 Hz), 2.43 (2H, t, J=8.0 Hz), 2.10 (2H, quintet, J=8.4 Hz), 1.93 (2H, quintet, J=7.2 Hz).

Example 237 Tert-Butyl 4-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Prepared according to general procedure 3 from 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and tert-butyl 4-am inopiperidine-1-carboxylate. LCMS [M+H]⁺ 398; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=6.8 Hz), 7.13 (1H, t, J=7.6 Hz), 7.08 (1H, dd, J=7.2 and 0.8 Hz), 5.82 (1H, s), 4.07-4.05 (2H, m), 2.99 (2H, m), 2.33 (3H, s), 2.22 (3H, s), 2.03-1.99 (2H, s), 1.49 (9H, s), 1.42-1.39 (2H, m).

Example 238 Ethyl 4-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)piperidine-1-carboxylate

Prepared according to general procedure 3 from 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and ethyl 4-am inopiperidine-1-carboxylate. LCMS [M+H]⁺ 370; ¹H NMR (400 MHz, CD₃OD) δ_(H) 7.19 (1H, d, J=7.2 Hz), 7.11 (1H, t, J=7.2 Hz), 7.08 (1H, d, J=7.6 Hz), 5.82 (1H, s), 4.15 (2H, q, J=7.2 Hz), 4.15-4.09 (3H, m), 3.07-2.98 (2H, m), 2.33 (3H, s), 2.21 (3H, s), 2.04-2.01 (2H, m), 1.48-1.39 (2H, m), 1.29 (4H, t, J=7.2 Hz).

Example 239 Tert-Butyl (3-((2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl)amino)-2,2-dimethyl-propyl)carbamate

Prepared according to general procedure 3 from 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine and tert-butyl N-(3-amino-2,2-dimethylpropyl)carbamate. LCMS [M+H]⁺ 400.

Example 240 6-(5-chloro-4-methoxy-2-methylphenyl)-4-N-methylpyrimidine-2,4-diamine

Prepared according to general procedure 6 from (5-chloro-4-methoxy-2-methylphenyl)boronic acid and 6-iodo-4-N-methylpyrimidine-2,4-diamine. LCMS [M+H]⁺ 279.

Example 241 6-(3-chloro-2-methylphenyl)-4-N-[(1R)-1-phenylethyl]pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol) and (+)1-phenylethan-1-amine (0.050 mL) were stirred neat at 150° C. for 1 hour. The crude material was dissolved in MeOH (2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 339; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 9.25 (1H, d, J=8.08 Hz) 7.62-7.71 (1H, m) 7.24-7.47 (7H, m) 6.23 (0.1H, s) 6.09 (0.9H, s) 5.35 (1H, quin, J=7.26 Hz) 2.31 (2.7H, s) 2.13 (0.3H, s) 1.46-1.57 (3H, m).

Example 242 6-(3-chloro-2-methylphenyl)-4-N-(2-phenylpropan-2-yl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol) and 2-phenylpropan-2-amine (0.050 mL) were stirred neat at 150° C. for 24 hours. The crude material was dissolved in MeOH (2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 353; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.45 (1H, br. s.) 8.96 (1H, br. s.) 7.12-7.79 (8H, m) 6.22 (1H, s) 2.31 (3H, s) 1.79 (6H, br. s.)

Example 243 6-(3-chloro-2-methylphenyl)-4-N-[1-(1H-indol-3-yl)propan-2-yl]pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol) and 1-(1H-indol-3-yl)propan-2-amine (0.050 mL) were stirred neat at 150° C. for 1 hour. The crude material was dissolved in MeOH (2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 392; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.34 (1H, br. s.) 10.90 (0.9H, s) 10.85 (0.1H, br. s.) 8.79 (0.9H, d, J=7.83 Hz) 8.63 (0.1H, d, J=9.09 Hz) 7.66 (0.9H, dd, J=7.20, 2.15 Hz) 7.62 (0.1 H, d, J=7.58 Hz) 7.54 (1H, d, J=7.83 Hz) 7.28-7.43 (3H, m) 7.20 (0.9H, d, J=2.27 Hz) 6.95-7.13 (2H, m) 6.89-6.95 (0.1H, m) 5.99 (0.9H, s) 5.93 (0.1H, s) 4.39-4.50 (1H, m) 2.86-3.03 (2H, m) 2.30 (2.7H, s) 2.14 (0.3H, s) 1.27 (0.3H, d, J=6.32 Hz) 1.20 (2.7H, d, J=6.57 Hz).

Example 244 4-N-{bicyclo[2.2.1]heptan-2-yl}-6-(3-chloro-2-methylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol) and bicyclo[2.2.1]heptan-2-amine (0.050 mL) were stirred neat at 150° C. for 1 hour. The crude material was dissolved in MeOH (˜2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 329; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 8.66 (1H, br. s.) 7.62-7.69 (1H, m) 7.35-7.44 (2H, m) 5.99 (1H, s) 3.87 (1H, br. s.) 2.30 (3H, s) 2.27-2.35 (1H, m) 2.24 (1H, d, J=3.28 Hz) 1.70-1.80 (1H, m) 1.33-1.60 (4H, m) 1.09-1.26 (3H, m)

Example 245 6-(3-chloro-2-methylphenyl)-4-N-ethylpyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol), 70% ethanamine (0.050 mL) and n-butanol (2 mL) were stirred in a sealed tube at 120° C. for 8 hours. The solvent was removed in vacuo and the crude material was dissolved in MeOH (2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 263; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.49 (1H, br. s.) 8.86 (0.9H, t, J=5.18 Hz) 8.63-8.73 (0.1H, m) 7.60-7.70 (1H, m) 7.34-7.45 (2H, m) 6.34 (0.1H, br. s.) 6.02 (0.9H, s) 3.23-3.58 (2H, m) 2.33 (0.3H, s) 2.30 (2.7H, s) 1.18 (2.7H, t, J=7.20 Hz) 1.08-1.14 (0.3H, m)

Example 246 6-(3-chloro-2-methylphenyl)-4-N-(propan-2-yl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (25 mg, 0,098 mmol), propan-2-amine (0.050 mL) and n-butanol (2 mL) were stirred in a sealed tube at 120° C. for 8 hours. The solvent was removed in vacuo and the crude material was dissolved in MeOH (2 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 277.

Example 247 4-N-[2-(2-chlorophenoxyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (13 mg, 0,054 mmol) and 1-(2-aminoethoxy)-2-chlorobenzene (18 mg, 0.11 mmol) were stirred neat at 150° C. for 1 h. The crude material was dissolved in MeOH (1 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 369.

Example 248 4-N-[2-(5-chloro-1H-1,3-benzodiazol-2-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), 2-(5-chloro-1H-1,3-benzodiazol-2-yl)ethan-1-amine (20 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 393.

Example 249 4-N-[2-(2,5-dimethyl-1H-indol-3-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol) and 2-(2,5-dimethyl-1H-indol-3-yl)ethan-1-amine (0.020 mL) were stirred neat at 150° C. for 1 hour. The crude material was dissolved in MeOH (1 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 386; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.30 (1H, br. s.) 10.65 (0.9H, s) 10.60 (0.1H, s) 8.82 (0.9H, t, J=5.56 Hz) 8.56-8.67 (0.1H, m) 7.06-7.41 (5H, m) 6.70-6.85 (1H, m) 5.97 (0.9H, s) 5.76 (0.1H, s) 3.58 (1.8H, q, J=6.65 Hz) 3.48 (0.2H, d, J=6.32 Hz) 2.93 (0.8H, t, J=7.07 Hz) 2.80-2.89 (0.2H, m) 2.23-2.38 (9H, m) 2.17 (2.7H, s) 2.06 (0.3H, s)

Example 250 6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yloxy)propyl]pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol) and 3-[(1-aminopropan-2-yl)oxy]pyridine (15 mg, 0.10 mmol) were stirred neat at 150° C. for 1 h. The crude material was dissolved in MeOH (1 mL) and purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 350.

Example 251 6-(2,3-dimethylphenyl)-4-N-(1H-indazol-5-ylmethyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol), 1H-indazol-5-ylmethanamine (15 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 345.

Example 252 6-(2,3-dimethylphenyl)-4-N-(1H-indazol-6-ylmethyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol), 1H-indazol-6-ylmethanamine (15 mg, 0.10 mmol), Et3N (0.040 mL), 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 h. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 345

Example 253 6-(2,3-dimethylphenyl)-4-N-[(2-methoxypyridin-4-yl)methyl]pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol), (2-methoxypyridin-4-yl)methanamine (14 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 336.

Example 254 4-N-[(5-chloropyrazin-2-yl)methyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol), (5-chloropyrazin-2-yl)methanamine (14 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 341.

Example 255 6-(2,3-dimethylphenyl)-4-N-{imidazo[1,2-a]pyridin-2-ylmethyl}pyrimidine-2,4-diamine

4-Chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (12 mg, 0,050 mmol), imidazo[1,2-a]pyridin-2-ylmethanamine (14 mg, 0.10 mmol), Et₃N (0.040 mL, 0.30 mmol) and 1-butanol (0.20 mL) were stirred at 100° C. for 20 hours. MeOH (1 mL) was added and the mixture was purified by preparative HPLC to give the desired product. LCMS [M+H]⁺ 345.

Example 256 Tert-butyl 4-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-(methoxymethyl)phenoxymethyl}piperidine-1-carboxylate

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), tert-butyl 4-[4-(dimethoxyboranyl)-2-(methoxymethyl)phenoxymethyl]piperidine-1-carboxylate (67 mg, 0.17 mmol), potassium carbonate (41 mg, 0.30 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (5 mL) and water (1.5 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 458.

Example 257 6-[3-(methoxymethyl)-4-(piperidin-4-ylmethoxy)phenyl]-4-N-methylpyrimidine-2,4-diamine hydrochloride

A solution of tert-butyl 4-{4-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-(methoxymethyl)-phenoxymethyl}piperidine-1-carboxylate (45 mg, 0.10 mmol; Example 256) in methanol (3 mL) was treated with 4M HCl in 1,4-dioxane (1 mL). The mixture was stirred at r.t. for 3 h, concentrated and dried in vacuo to give the desired product. LCMS [M+H]⁺ 358.

Example 258 3-[2-amino-6-(methylamino)pyrimidin-4-yl]-2-methylbenzonitrile

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), (3-cyano-2-methylphenyl)boronic acid (29 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 240.

Example 259 6-(4-methoxy-2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), (4-methoxy-2,3-dimethylphenyl)boronic acid (32 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 259.

Example 260 6-(4-fluoro-2,3-dimethylphenyl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), (4-fluoro-2,3-dimethylphenyl)boronic acid (30 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 247.

Example 261 6-(2,3-dihydro-1-benzofuran-7-yl)-4-N-methylpyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), (2,3-dihydro-1-benzofuran-7-yl)boronic acid (30 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 243.

Example 262 4-N-methyl-6-[2-methyl-5-(morpholine-4-sulfonyl)phenyl]pyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (24 mg, 0.15 mmol), [2-methyl-5-(morpholine-4-sulfonyl)phenyl]boronic acid (51 mg, 0.18 mmol), potassium carbonate (41 mg, 0.30 mmol) and tetrakis(triphenylphosphine)-palladium (0) (9 mg, 0.008 mmol) in 1,4-dioxane (3 mL) and water (1 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 364.

Example 263 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (28 mg, 0.10 mmol), 2-(4-chlorophenyl)ethan-1-amine (22 mg, 0.14 mmol) and Hünig's base (36 μL, 0.20 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 393. 1H NMR (400 MHz, DMSO-d6) δ_(H) ppm 12.56 (br. s., 1H), 8.90 (br. s., 1H), 7.83-7.89 (m, 1H), 7.51-7.59 (m, 2H), 7.35-7.41 (m, 2H), 7.28-7.34 (m, 2H), 6.11 (s, 1H), 3.63 (q, J=6.4 Hz, 2H), 2.89 (t, J=7.1 Hz, 2H).

Example 264 4-N-[2-(4-chlorophenyl)ethyl]-6-(2-methylphenyl)pyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg, 0.12 mmol), (2-methylphenyl)boronic acid (20 mg, 0.14 mmol), potassium carbonate (33 mg, 0.24 mmol) and palladium tetrakis(triphenylphosphine)-palladium (0) (7 mg, 0.006 mmol) in 1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 339.

Example 265 4-N-[2-(4-chlorophenyl)ethyl]-6-[3-(trifluoromethyl)phenyl]pyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg, 0.12 mmol), [3-(trifluoromethyl)phenyl]boronic acid (27 mg, 0.14 mmol), potassium carbonate (33 mg, 0.24 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) in 1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 393.

Example 266 4-N-[2-(4-chlorophenyl)ethyl]-6-(quinolin-5-yl)pyrimidine-2,4-diamine

A mixture of 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine (34 mg, 0.12 mmol), (quinolin-5-yl)boronic acid (25 mg, 0.14 mmol), potassium carbonate (33 mg, 0.24 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol) in 1,4-dioxane/water (4 mL; 4:1) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 376.

Example 267 4-N-[2-(4-chlorophenyl)cyclopropyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), 2-(4-chlorophenyl)cyclopropan-1-amine (43 mg, 0.26 mmol) and Hünig's base (90 μL, 0.52 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 365.

Example 268 6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), 2-(pyridin-3-yl)ethan-1-amine (21 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 320.

Example 269 3-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)phenol

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), 3-(2-aminoethyl)phenol (23 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 335.

Example 270 6-(2,3-dimethylphenyl)-4-N-[3-(morpholin-4-yl)propyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), 3-(morpholin-4-yl)propan-1-amine (24 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 342.

Example 271 Tert-butyl N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), tert-butyl N-(2-aminoethyl)carbamate (27 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 358.

Example 272 N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)acetamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), N-(2-aminoethyl)acetamide (17 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 300.

Example 273 Benzyl N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), benzyl N-(2-aminoethyl)carbamate hydrochloride (39 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 392.

Example 274 Tert-butyl N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N-methylcarbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), tert-butyl N-(2-aminoethyl)-N-methylcarbamate (29 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 372.

Example 275 Tert-butyl N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-carbamate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), tert-butyl N-(3-aminopropyl)carbamate (29 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 372.

Example 276 6-(2,3-dimethylphenyl)-4-N-[3-(5-methyl-1H-pyrazol-3-yl)propyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (28 mg, 0.12 mmol), 3-(5-methyl-1H-pyrazol-4-yl)propan-1-amine (23 mg, 0.17 mmol) and Hünig's base (42 μL, 0.24 mmol) in n-butanol (2 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 337.

Example 277 3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-1-(morpholin-4-yl)propan-1-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), 3-amino-1-(morpholin-4-yl)propan-1-one (22 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC.

LCMS [M+H]⁺ 356.

Example 278 4-N-[(4-benzylmorpholin-2-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), (4-benzylmorpholin-2-yl)methanamine (29 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC.

LCMS [M+H]⁺ 404.

Example 279 6-(2,3-dimethylphenyl)-4-N-[(4-methanesulfonylphenyl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), (4-methanesulfonylphenyl)methanamine hydrochloride (31 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 383.

Example 280 6-(2,3-dimethylphenyl)-4-N-{[4-(4-methylpiperazin-1-yl)phenyl]methyl}pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), [4-(4-methylpiperazin-1-yl)phenyl]methanamine (29 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 403.

Example 281 4-N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), (S)-quinuclidin-3-amine hydrochloride (29 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 324.

Example 282 Tert-butyl 2-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-pyrrolidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate (28 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 398.

Example 283 Tert-butyl 4-({[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-piperidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (23 mg, 0.10 mmol), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (30 mg, 0.14 mmol) and Hünig's base (35 μL, 0.20 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 85° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 412.

Example 284 1-(3-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (19 mg, 0.070 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (49 μL, 0.35 mmol) in n-butanol (1 mL) was heated in a sealed tube at 110° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 380.

Example 285 1-(3-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (19 mg, 0.076 mmol) and 1-(3-aminopropyl)pyrrolidin-2-one (53 μL, 0.38 mmol) in n-butanol (1 mL) was heated in a sealed tube at 110° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 360.

Example 286 1-(3-{[2-amino-6-(4-fluoro-2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (4-fluoro-2,3-dimethylphenyl)boronic acid (18 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 358.

Example 287 1-(3-{[2-amino-6-(4-methoxy-2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (4-methoxy-2,3-dimethylphenyl)boronic acid (20 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 370.

Example 288 1-(3-{[2-amino-6-(4-methyl-1H-indazol-5-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (4-methyl-1H-indazol-5-yl)boronic acid (19 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 366.

Example 289 1-[3-({2-amino-6-[2-methyl-5-(morpholine-4-sulfonyl)phenyl]pyrimidin-4-yl}amino)propyl]pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), [2-methyl-5-(morpholine-4-sulfonyl)phenyl]boronic acid (31 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 475.

Example 290 1-(3-{[2-amino-6-(2,3-dihydro-1-benzofuran-7-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (2,3-dihydro-1-benzofuran-7-yl)boronic acid (18 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 354.

Example 291 1-(3-{[2-amino-6-(2,5-dimethylphenyl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (2,5-dimethylphenyl)boronic acid (17 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 340.

Example 292 1-(3-{[2-amino-6-(5-chloro-2-methylphenyl) pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (5-chloro-2-methylphenyl)boronic acid (19 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenyl-phosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 360.

Example 293 1-[3-({2-amino-6-[2-(trifluoromethyl)phenyl]pyrimidin-4-yl}amino)propyl]pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), [2-(trifluoromethyl)phenyl]boronic acid (21 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis-(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 380.

Example 294 1-(3-{[2-amino-6-(1H-indol-4-yl)pyrimidin-4-yl]amino}propyl)pyrrolidin-2-one

A mixture of 1-{3-[(2-amino-6-chloropyrimidin-4-yl)amino]propyl}pyrrolidin-2-one (27 mg, 0.10 mmol), (1H-indol-4-yl)boronic acid (18 mg, 0.11 mmol), potassium carbonate (28 mg, 0.20 mmol) and palladium tetrakis(triphenylphosphine)-palladium (0) (6 mg, 0.005 mmol) in 1,4-dioxane (4 mL) and water (1 mL) was heated in a sealed tube at 95° C. for 2 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 351.

Example 295 4-N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (47 mg, 0.20 mmol), [1-(4-chlorophenyl)cyclopropyl]methanamine hydrochloride (65 mg, 0.30 mmol) and Hünig's base (70 μL, 0.40 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 130° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 379.

Example 296 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (41 mg, 0.15 mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (45 mg, 0.23 mmol) and Hünig's base (39 μL, 0.23 mmol) in n-butanol (2 mL) was heated in a sealed tube at 90° C. for 48 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 438.

Example 297 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(3-chloro-2-methylphenyl)pyrimidin-2-amine (38 mg, 0.15 mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (45 mg, 0.23 mmol) and Hünig's base (39 μL, 0.23 mmol) in n-butanol (2 mL) was heated in a sealed tube at 90° C. for 48 h. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 418. 1H NMR (400 MHz, DMSO-d6) δ_(H) ppm 12.33 (br. s., 1H), 8.89 (br. s., 1H), 7.77 (d, J=8.1 Hz, 2H), 7.64-7.68 (m, 1H), 7.48 (d, J=8.1 Hz, 2H), 7.37-7.41 (m, 2H), 7.32 (s, 2H), 6.03 (s, 1H), 3.67 (q, J=6.7 Hz, 2H), 2.98 (t, J=7.1 Hz, 2H), 2.30 (s, 3H).

Example 298 4-N-(Adamantan-1-yl)-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A mixture of the 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg) and adamantylamine (50 mg) was heated at 150° C. for 1 h. The mixture was cooled, diluted in methanol then purified by preparative HPLC. LCMS [M+H]⁺ 389.

Example 299 6-(2,3-dichlorophenyl)-4-N-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg) and (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (50 mg) was heated at 150° C. for 1 h. The mixture was cooled, diluted in methanol then purified by preparative HPLC. LCMS [M+H]⁺ 391.

Example 300 6-(2,3-Dichlorophenyl)-4-N-({3-[(4-methylpiperidin-1-yl)methyl]phenyl}methyl)-pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg) and {3-[(4-methylpiperidin-1-yl)methyl]phenyl}methanamine (50 mg) was heated at 150° C. for 1 h. The mixture was cooled, diluted in methanol and then purified by preparative HPLC. LCMS [M+H]⁺ 456.

Example 301 4-(2-{[2-Amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)phenol

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg) and 4-(2-aminoethyl)phenol (50 mg) was heated at 150° C. for 1 h. The mixture was cooled, diluted in methanol then purified by preparative HPLC. LCMS [M+H]⁺ 375.

Example 302 Ethyl 4-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}piperidine-1-carboxylate

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg) and ethyl 4-aminopiperidine-1-carboxylate (50 mg) was heated at 150° C. for 1 h. The mixture was cooled, diluted in methanol then purified by preparative HPLC. LCMS [M+H]⁺ 410.

Example 303 N-(4-{[2-Amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}butyl)acetamide

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg; 0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with N-(4-aminobutyl)acetamide (1 eq.) and triethylamine (1 eq). After 18 h the reaction was halted and evaporated. The residue was purified by preparative HPLC. LCMS [M+H]⁺ 368.

Example 304 6-(2,3-Dichlorophenyl)-4-N-{tricyclo[3.3.1.0^(3,7)]nonan-3-yl}pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg; 0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with tricyclo[3.3.1.0^(3,7)]nonan-3-amine (1 eq) and triethylamine (1 eq). After 18 h the reaction was halted and evaporated. The residue was purified by preparative HPLC. LCMS [M+H]⁺ 375.

Example 305 6-(2,3-Dichlorophenyl)-4-N-{[4-(1,2,3-thiadiazol-4-yl)phenyl]methyl}pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg; 0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with [4-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (1 eq) and triethylamine (1 eq). After 18 h the reaction was halted and evaporated. The residue was purified by preparative HPLC. LCMS [M+H]⁺ 429.

Example 306 4-N-[2-(1-Benzylpiperidin-4-yl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg; 0.1 mmol) in n-BuOH (1.0 ml) was heated at 130° C. with 2-(1-benzylpiperidin-4-yl)ethan-1-amine (1 eq) and triethylamine (1 eq). After 18 h the reaction was halted and evaporated. The residue was purified by preparative HPLC. LCMS [M+H]⁺ 456.

Example 307 6-(2,3-Dichlorophenyl)-4-N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)pyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (25 mg; 0.1 mmol) in n-BuOH (1.0 ml) was heated at 130 degrees with 2,3-dihydro-1,4-benzodioxin-2-ylmethanamine (1 eq) and triethylamine (1 eq). After 18 h the reaction was halted and evaporated. The residue was purified by preparative HPLC. LCMS [M+H]⁺ 403.

Example 308 N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}-3-hydroxypyridine-2-carboxamide

Equimolar quantities of 3-hydroxypyridine-2-carboxylic acid (0.24 mmol) and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine were dissolved in 2 ml DMF followed by addition of hydroxybenzotriazole (1.0 eq) and N,N′-dicyclohexylcarbodiimide (1.5 eq). The solution was stirred at rt overnight. The mixture was then filtrated and purified by preparative HPLC.

LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.15 (1H, br. s.), 11.17 (1H, s), 8.86 (1H, m, J=5.05 Hz), 8.25-8.35 (2H, m), 8.03 (1H, dd, J=8.08, 1.26 Hz), 7.59-7.68 (2H, m), 7.52 (2H, dd, J=8.46, 1.39 Hz), 6.36 (1H, s), 2.95 (3H, d, J=4.80 Hz).

Example 309 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enamide

To a stirred suspension of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.29 mmol) and triethylamine (1.5 eq.) in acetonitrile (2 mL) at 0° C. was slowly added prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 270; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.35 (1H, s), 8.23 (1H, t, J=1.89 Hz), 7.79 (1H, d, J=8.08 Hz), 7.56-7.69 (4H, m), 7.34-7.52 (4H, m), 6.88 (1H, s), 6.84 (1H, s), 6.18 (1H, s), 5.98 (2H, s), 2.80 (3H, d, J=4.80 Hz).

Example 310 (2E)-N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-3-phenylprop-2-enamide

To a suspension of the 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.25 mmol) and triethylamine (1.5 eq.) in acetonitrile (2 mL) at 0° C. was added drop wise, with stirring, the (E)-3-phenylprop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt, and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 346; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.35 (s, 1H), 8.23 (t, J=1.89 Hz, 1H), 7.79 (d, J=8.08 Hz, 1H), 7.56-7.69 (m, 4H), 7.34-7.52 (m, 4H), 6.88 (s, 1H), 6.84 (s, 1H), 6.18 (s, 1H), 5.98 (s, 2H), 2.80 (d, J=4.80 Hz, 3H).

Example 311 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]-2-methylphenyl}prop-2-enamide

To a suspension of 6-(3-amino-2-methyl-phenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.39 mmol) and triethylamine (1.5 eq.) in acetonitrile (3 ml) at 0° C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt, and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 9.57 (1H, s), 7.41 (1H, d, J=7.58 Hz), 7.20 (1H, t, J=7.83 Hz), 7.10 (1H, d, J=6.82 Hz), 6.83 (1H, br. s.), 6.54 (1H, dd, J=17.05, 10.23 Hz), 6.25 (1H, dd, J=17.05, 2.15 Hz), 5.97 (2H, s), 5.73-5.78 (1H, m), 5.71 (1H, s), 2.77 (3H, d, J=4.55 Hz), 2.14 (3H, s).

Example 312 (2E)-N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-4-(dimethylamino)but-2-enamide

To a solution of 6-(3-aminophenyl)-4-N-methylpyrimidine-2,4-diamine (0.29 mol) in acetonitrile (4 mL) was added successively (E)-4-(dimethylamino)but-2-enoic acid; hydrochloride (1.0 eq.), triethylamine (3.0 eq.) and n-propanephosphonic acid anhydride (T3P, 2.0 eq.). The resulting mixture was stirred at rt overnight. The solution was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 327; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.17 (1H, s), 8.20 (1H, t, J=1.77 Hz), 7.71 (1H, d, J=8.08 Hz), 7.58 (1H, d, J=7.83 Hz), 7.36 (1H, t, J=7.83 Hz), 6.81-6.96 (1H, m), 6.70-6.80 (1H, m), 6.28 (1H, dt, J=15.35, 1.55 Hz), 6.16 (1H, s), 5.97 (2H, s), 3.06 (2H, dd, J=6.06, 1.52 Hz), 2.79 (3H, d, J=4.80 Hz), 2.18 (6H, s).

Example 313 N-{3-[2-amino-6-(methylamino)pyrimidin-4-yl]phenyl}ethene-1-sulfonamide

To a suspension of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.20 mmol) and triethylamine (1.1 eq.) in acetonitrile (1.5 mL) at −60° C. was added drop wise, with stirring, ethenesulfonyl chloride (0.9 eq.) in 0.5 ml acetonitrile. The mixture was allowed to warm to rt, and stirred for 2 h. The solution was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 306; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 11.98 (1H, br. s.), 10.38 (1H, br. s.), 8.79 (1H, br. s.), 7.31-7.60 (4H, m), 6.85 (1H, dd, J=16.42, 9.85 Hz), 6.25 (1H, s), 6.18 (1H, d, J=16.42 Hz), 6.08 (1H, d, J=9.85 Hz), 2.93 (3H, d, J=4.80 Hz).

Example 314 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-ynamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.30 mol) in acetonitrile (5 mL) at 0° C. was added successively prop-2-ynoic acid (1.0 eq.), triethylamine (2.0 eq.) and n-propanephosphonic acid anhydride (T3P, 1.7 eq.). The resulting mixture was stirred at rt overnight. The solution was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 268; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 8.19 (1H, br. s.), 7.84 (1H, d, J=7.83 Hz), 7.65 (1H, d, J=7.83 Hz), 7.46 (1H, d, J=13.39 Hz), 7.38 (1H, t, J=7.83 Hz), 7.00 (1H, d, J=13.89 Hz), 6.28 (1H, br. s.), 5.97 (2H, s), 2.78 (3H, d, J=4.55 Hz).

Example 315 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-oxopropanamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.39 mol) in acetonitrile (4 mL) was added successively pyruvic acid (1.0 eq.), triethylamine (2.5 eq.) and n-propanephosphonic acid anhydride (T3P, 2.0 eq.). The resulting mixture was stirred at rt overnight. The solution was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 286.

Example 316 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-oxo-2-phenylacetamide

To a solution of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.42 mol) in acetonitrile (4 mL) was added successively 2-oxo-2-phenyl-acetic acid (0.9 eq.), triethylamine (2.5 eq.) and n-propanephosphonic acid anhydride (T3P, 2.0 eq.). The resulting mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 348; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 8.30-8.36 (1H, m), 8.00-8.11 (2H, m), 7.66-7.84 (3H, m), 7.59-7.66 (2H, m), 7.45 (1H, t, J=7.96 Hz), 6.90 (1H, br. s.), 6.19 (1H, s), 6.01 (2H, s), 2.80 (3H, d, J=4.80 Hz).

Example 317 N-{4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}prop-2-enamide

To a suspension of 6-(4-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.29 mmol) and triethylamine (1.5 eq.) in tetrahydrofuran (2 ml) at 0° C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt, and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 270; ¹H NMR (400 MHz, DMSO-d6) δ_(H) ppm 10.28 (1H, s), 7.89 (2H, d, J=8.8 Hz), 7.58-7.75 (2H, m), 6.76 (1H, br. s.), 6.40-6.49 (1H, m), 6.24-6.30 (1H, m), 6.17 (1H, s), 5.94 (2H, s), 5.58-5.80 (1H, m), 2.79 (3H, d, J=4.8 Hz).

Example 318 N-({4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}methyl)prop-2-enamide

To a suspension of 6-[4-(aminomethyl)phenyl]-4-N-methyl-pyrimidine-2,4-diamine (0.29 mmol) and triethylamine (1.5 eq.) in tetrahydrofuran (2 ml) at 0° C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284.

Example 319 N-({3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}methyl)prop-2-enamide

To a suspension of 6-[3-(aminomethyl)phenyl]-4-N-methyl-pyrimidine-2,4-diamine (0.16 mmol) and triethylamine (1.5 eq.) acetonitrile (4 mL) at 0° C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to room temperature, and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284.

Example 320 N-{3-[2-Amino-6-(ethylamino)pyrimidin-4-yl]-4-methylphenyl}prop-2-enamide

To a suspension of 6-(5-amino-2-methyl-phenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.48 mmol) and triethylamine (1.7 eq.) in acetonitrile (3 mL) at 0° C. was added drop wise, with stirring, prop-2-enoyl chloride (1.0 eq.). The mixture was allowed to warm to rt and stirred for 3 h. The mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 284; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.10 (1H, s), 7.46-7.75 (2H, m), 7.16 (1H, d, J=8.34 Hz), 6.80 (1H, br. s.), 6.37-6.46 (1H, m), 6.23 (1H, dd, J=17.05, 2.15 Hz), 5.95 (2H, s), 5.62-5.84 (2H, m), 2.77 (3H, d, J=4.55 Hz), 2.27 (3H, s).

Example 321 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-5-chloro-2-hydroxybenzamide

Equimolar quantities of 5-chloro-2-hydroxy-benzoic acid and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) were dissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq) and N,N′-dicyclohexylcarbodiimide (1.5 eq). The solution was stirred under rt overnight. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 370; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 15.10 (1H, br. s), 8.08-8.16 (1H, m), 7.86 (1H, d, J=7.58 Hz), 7.64 (1H, d, J=3.03 Hz), 7.49 (1H, d, J=7.33 Hz), 7.32 (1H, t, J=7.96 Hz), 6.93 (1H, dd, J=8.84, 3.03 Hz), 6.78-6.89 (1H, m), 6.40 (1H, d, J=8.84 Hz), 6.20 (1H, s), 6.03 (2H, s), 2.80 (3H, d, J=4.55 Hz).

Example 322 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxyacetamide

Equimolar quantities of 2-hydroxyacetic acid and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) were dissolved in 2 ml DMF followed by adding hydroxybenzotriazole (1.0 eq) in 1 mL DMF and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved in xylene). The solution was stirred under room temperature overnight. The mixture was then filtrated and purified by preparative. LCMS [M+H]⁺ 274; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.06 (1H, br. s.), 9.75-10.10 (1H, m), 8.83 (1H, d, J=4.55 Hz), 8.22 (1H, s), 7.84 (1H, d, J=9.35 Hz), 7.54 (1H, t, J=7.96 Hz), 7.40 (1H, d, J=8.08 Hz), 6.30 (1H, s), 5.61-5.97 (1H, m), 4.03 (2H, s), 2.94 (3H, d, J=4.80 Hz).

Example 323 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-(4-chlorophenyl)-2-hydroxyacetamide

Equimolar quantities of 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) and 2-(4-chlorophenyl)-2-hydroxy-acetic acid were dissolved in 2 ml DMF followed by adding hydroxybenzotriazole (1.0 eq) in 1 mL DMF and N,N′-dicyclohexylcarbodiimide (1.5 eq.; as a solution in xylene). The solution was stirred at rt overnight. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 384; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 10.05 (1H, s), 8.22 (1H, t, J=1.89 Hz), 7.69 (1H, d, J=8.59 Hz), 7.59 (1H, d, J=6.57 Hz), 7.52-7.57 (2H, m), 7.40-7.45 (2H, m), 7.34 (1H, t, J=7.96 Hz), 6.85 (1H, br. s.), 6.14 (1H, s), 6.04 (2H, br. s.), 5.97 (1H, s), 5.14 (1H, s), 2.78 (3H, d, J=4.80 Hz).

Example 324 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxy-2-phenylacetamide

Equimolar quantities of 2-hydroxy-2-phenyl-acetic acid and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) were dissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq) in DMF (1 mL) and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved in xylene). The solution was stirred under rt overnight. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 350; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 11.86 (1H, br. s.), 10.25 (2H, s), 8.25 (1H, s), 7.85 (1H, d, J=8.59 Hz), 7.48-7.63 (3H, m), 7.26-7.46 (4H, m), 6.56 (1H, d, J=4.29 Hz), 6.28 (1H, s), 5.15 (1H, d, J=3.79 Hz), 2.93 (3H, d, J=4.80 Hz).

Example 325 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-4-oxo-4-(pyrrolidin-1-yl)butanamide

Equimolar quantities of 4-oxo-4-pyrrolidin-1-yl-butanoic acid and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) were dissolved in DMF (2 mL) followed by adding hydroxybenzotriazole (1.0 eq) in DMF (1 mL) and N,N′-dicyclohexylcarbodiimide (1.5 eq, dissolved in xylene). The solution was stirred at rt overnight. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 369.

Example 326 N-{3-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2-hydroxybenzamide

Equimolar quantities of 2-hydroxybenzoic acid and 6-(3-aminophenyl)-4-N-methyl-pyrimidine-2,4-diamine (0.24 mmol) were dissolved in MeCN (2 mL) followed by adding N,N′-dicyclohexylcarbodiimide (1.25 eq). The solution was stirred at rt overnight. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 336.

Example 327 1-{4-[2-Amino-6-(methylamino)pyrimidin-4-yl]phenyl}-2,2,2-trifluoroethan-1-one

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (0.25 mmol), [4-(trifluoroacetyl)phenyl]boronic ester (1.3 eq.), sodium carbonate (3.2 eq.), dioxane (2 mL) and water (0.5 mL) in a tube. The tube was sealed and the reaction was heated at 90° C. for 5 hours. The mixture was then filtrated and purified by preparative HPLC. LCMS [M+H]⁺ 297.

Example 328 6-[3-(Aminomethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (2.00 mmol), [3-(aminomethyl)phenyl]boronic acid (1.3 eq.), sodium carbonate (3.2 eq.), dioxane (4 mL) and water (1 mL) in a tube. The tube was sealed and the reaction was heated at 90° C. overnight. The solvent were removed in vacuum and to the remaining solid was added ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. The crude material was then purified by flash chromatography (0→15% MeOH/DCM) to give the title compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 7.90 (1H, s), 7.75 (1H, d, J=6.32 Hz), 7.35-7.42 (3H, m), 6.82 (1H, br. S), 6.21 (1H, s), 5.98 (2H, s), 3.79 (2H, s), 2.79 (3H, d, J=4.80 Hz).

Example 329 6-[4-(Aminomethyl)phenyl]-4-N-methylpyrimidine-2,4-diamine

Tetrakis(triphenylphosphine)palladium (0) (5 mol %) was added to a stirred mixture of 6-chloro-4-N-methylpyrimidine-2,4-diamine (1.00 mmol), [4-(aminomethyl)phenyl]boronic acid (1.3 eq.), sodium carbonate (4.2 eq.), dioxane (4 ml) and water (1 ml) in a tube. The tube was sealed and the reaction was heated at 90° C. overnight. The solvent were removed in vacuum and to the remaining solid was added ethyl acetate and washed with water. The organic phase was dried over magnesium sulfate. The crude material was then purified by flash chromatography (0→15% MeOH/DCM) to give the title compound. LCMS [M+H]⁺ 230; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 7.86 (2H, d, J=7.58 Hz), 7.38 (2H, d, J=8.59 Hz), 6.19 (1H, s), 5.96 (2H, s), 3.76 (2H, s), 2.79 (3H, d, J=4.80 Hz).

Example 330 4-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.12 mmol), 4-(2-aminoethyl)benzene-1-sulfonamide (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 398; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.28 (1H, br. s.), 8.87 (1H, br. s.), 7.77 (2H, d, J=8.34 Hz), 7.48 (2H, d, J=8.34 Hz), 7.37 (1H, d, J=7.33 Hz), 7.32 (2H, s), 7.23-7.28 (1H, m), 7.18-7.23 (1H, m), 5.99 (1H, s), 3.67 (2H, q, J=6.82 Hz), 2.98 (2H, t, J=7.20 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 331 6-(2,3-Dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 2-(4-methanesulfonylphenyl)ethan-1-amine (1.2 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 397.

Example 332 6-(2,3-Dimethylphenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethan-1-amine (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 324.

Example 333 4-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzonitrile

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 4-(2-aminoethyl)benzonitrile (1.2 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 344; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.36 (1H, br. s.), 8.87 (1H, t, J=5.31 Hz), 7.80 (2H, d, J=8.08 Hz), 7.51 (2H, d, J=8.34 Hz), 7.37 (1H, d, J=7.33 Hz), 7.23-7.28 (1H, m), 7.16-7.22 (1H, m), 5.98 (1H, s), 3.67 (2H, q, J=6.65 Hz), 2.99 (2H, t, J=7.20 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 334 6-(2,3-Dimethylphenyl)-4-N-[2-(pyridin-4-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 2-(pyridin-4-yl)ethan-1-amine (1.2 eq.) and N,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 ml) was heated in a sealed tube at 110° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 320; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.45 (1H, br. s.), 8.93 (1H, t, J=5.56 Hz), 8.76 (2H, d, J=6.32 Hz), 7.80 (2H, d, J=6.32 Hz), 7.37 (1H, d, J=7.33 Hz), 7.25 (1H, t, J=7.58 Hz), 7.17-7.21 (1H, m), 5.99 (1H, s), 3.68-3.83 (2H, m), 3.13 (2H, t, J=7.07 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 335 4-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethoxy)benzonitrile

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 4-(2-aminoethoxyl)benzonitrile (1.2 eq.) and N,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 360; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 12.37 (1H, br. s.), 9.02 (1H, t, J=5.31 Hz), 7.77-7.83 (2H, m), 7.37 (1H, d, J=7.33 Hz), 7.23-7.29 (1H, m), 7.18-7.22 (1H, m), 7.12-7.18 (2H, m), 6.06 (1H, s), 4.29 (2H, t, J=5.43 Hz), 3.82 (2H, q, J=5.22 Hz), 2.31 (3H, s), 2.17 (3H, s).

Example 336 4-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)benzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.08 mmol), 4-(aminomethyl)benzene-1-sulfonamide (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 384; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 7.74-7.81 (2H, m), 7.49-7.54 (2H, m), 7.46 (1H, t, J=5.68 Hz), 7.30 (2H, s), 7.12-7.21 (1H, m), 7.01-7.12 (2H, m), 6.00 (2H, s), 5.76 (1H, br. s.), 4.57 (2H, br. s.), 2.26 (3H, s), 2.15 (3H, s).

Example 337 1-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-1,2-dihydropyridin-2-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.11 mmol), 1-(2-aminoethyl)-1,2-dihydropyridin-2-one (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 336.

Example 338 3-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)-1,2-dihydropyridin-2-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.11 mmol), 3-(aminomethyl)-1,2-dihydropyridin-2-one (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 ml) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 322.

Example 339 6-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.12 mmol), 6-(3-aminopropyl)-5H,6H,7H-pyrrolo[3,4-b]pyridin-5-one (0.9 eq.) and triethylamine (1.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 389.

Example 340 6-({[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}methyl)pyridin-3-ol

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.08 mmol), 6-(aminomethyl)pyridin-3-ol hydrochloride (0.9 eq.) and triethylamine (2.5 eq.) in acetonitrile/ethanol/methanol 5:3:2 (1 mL) was heated in a sealed tube at 95° C. overnight. Methanol was added, and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 322.

Example 341 4-N-[2-(3-Chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(3-chlorophenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 353; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.24 (s, 3H) 2.31 (s, 3H) 2.88 (t, J=7.07 Hz, 2H) 3.56 (d, J=5.81 Hz, 2H) 4.86-5.12 (m, 3H) 5.79 (s, 1H) 7.07-7.15 (m, 3H) 7.17 (q, J=4.04 Hz, 1H) 7.20-7.26 (m, 3H).

Example 342 6-(2,3-Dimethylphenyl)-4-N-[3-(1H-imidazol-1-yl)propyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 3-(1H-imidazol-1-yl)propan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 2.11 (t, J=6.82 Hz, 2H) 2.20 (s, 3H) 2.32 (s, 3H) 3.38 (br. s., 2H) 4.13 (t, J=6.95 Hz, 2H) 5.82 (s, 1H) 6.98 (br. s., 1H) 7.05-7.23 (m, 4H) 7.69 (br. s., 1H).

Example 343 4-N-[2-(4-Chlorophenyl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(4-chlorophenyl)propan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 367; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.31 (d, J=7.07 Hz, 3H) 2.23 (s, 3H) 2.31 (s, 3H) 2.97-3.09 (m, 1H) 3.28-3.40 (m, 1H) 3.46-3.66 (m, 1H) 4.74 (br. s., 1H) 4.95 (br. s., 2H) 5.74 (s, 1H) 7.09-7.14 (m, 2H) 7.14-7.19 (m, 3H) 7.28-7.33 (m, 2H).

Example 344 6-(2,3-Dimethylphenyl)-4-N-[2-(4-fluorophenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(4-fluorophenyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.29-2.34 (m, 3H) 2.89-2.96 (m, 3H) 3.49-3.60 (m, 1H) 3.76 (d, J=6.06 Hz, 3H) 5.77 (s, 4H) 7.00-7.07 (m, 3H) 7.08-7.12 (m, 2H) 7.13-7.22 (m, 5H) 7.28-7.32 (m, 1H).

Example 345 6-(2,3-Dimethylphenyl)-4-N-[2-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 418; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.74-1.81 (m, 4H) 2.22 (s, 3H) 2.30 (s, 3H) 2.46-2.69 (m, 5H) 3.49 (br. s., 2H) 3.81 (s, 3H) 4.88 (br. s., 2H) 5.04-5.18 (m, 1H) 5.74 (s, 1H) 6.85-6.90 (m, 2H) 7.09-7.12 (m, 2H) 7.13-7.17 (m, 1H) 7.24-7.29 (m, 2H).

Example 346 4-N-{[4-(Dimethylamino)phenyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-(aminomethyl)-N,N-dimethylaniline and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 348.

Example 347 4-N-[2-(Benzenesulfonyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(benzenesulfonyl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 383; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.31 (s, 3H) 3.41-3.46 (m, 2H) 3.86 (q, J=6.06 Hz, 2H) 5.10 (br. s., 2H) 5.41-5.53 (m, 1H) 5.76 (s, 1H) 7.07-7.16 (m, 2H) 7.16-7.20 (m, 1H) 7.57-7.63 (m, 2H) 7.66-7.71 (m, 1H) 7.92-7.97 (m, 2H),

Example 348 6-(2,3-Dimethylphenyl)-4-N-{[1-(4-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from [1-(4-fluorophenyl)-1H-pyrazol-4-yl]methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.29 (s, 3H) 4.47 (d, J=5.31 Hz, 2H) 5.11-5.41 (m, 3H) 5.85 (s, 1H) 7.10-7.19 (m, 5H) 7.59-7.65 (m, 2H) 7.68 (s, 1H) 7.85 (s, 1H)

Example 349 6-(2,3-dimethylphenyl)-4-N-{2-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 387.

Example 350 6-(2,3-Dimethylphenyl)-4-N-{[1-(pyrimidin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from [1-(pyrimidin-2-yl)piperidin-3-yl]methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 390; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.41 (m, 1H) 1.48-1.60 (m, 1H) 1.75 (m, 1H) 1.85-1.98 (m, 2H) 2.24 (s, 3H) 2.31 (s, 3H) 3.13-3.48 (m, 4H) 4.15-4.24 (m, 1H) 4.30 (m, 1H) 5.11 (br. s., 2H) 5.39 (br. s., 1H) 5.82 (s, 1H) 6.45 (t, J=4.80 Hz, 1H) 7.10-7.19 (m, 3H) 8.28-8.31 (d, J=4.80 Hz, 2H).

Example 351 6-(2,3-Dimethylphenyl)-4-N-[2-(6-methoxy-1H-1,3-benzodiazol-2-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(6-methoxy-1H-1,3-benzodiazol-2-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.16 (s, 3H) 2.24 (s, 3H) 3.12 (t, J=6.19 Hz, 2H) 3.81 (s, 3H) 3.82-3.90 (m, 2H) 5.11-5.43 (m, 2H) 5.79 (s, 1H) 5.88 (br. s., 1H) 6.85 (dd, J=8.72, 2.40 Hz, 1H) 7.01 (d, J=8.08 Hz, 2H) 7.05 (t, J=7.58 Hz, 1H) 7.12 (d, J=6.82 Hz, 1H) 7.40 (d, J=8.59 Hz, 1H).

Example 352 6-(2,3-Dimethylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(4-methyl-1,3-thiazol-5-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.30 (s, 3H) 2.40 (s, 3H) 3.07 (t, J=6.82 Hz, 2H) 3.56 (q, J=6.48 Hz, 2H) 5.01 (br. s., 3H) 5.79 (s, 1H) 7.11-7.14 (m, 2H) 7.17 (q, J=4.55 Hz, 1H) 8.59 (s, 1H).

Example 353 4-N-[(3-Cyclopropyl-1H-pyrazol-5-yl)methyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from (3-cyclopropyl-1H-pyrazol-5-yl)methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 335; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 0.63-0.71 (m, 2H) 0.93 (br. d, J=7.33 Hz, 2H) 1.83-1.93 (m, 1H) 2.18 (s, 3H) 2.31 (s, 3H) 4.50 (br. s., 2H) 5.86 (s, 1H) 5.92 (s, 1H) 7.03-7.22 (m, 3H).

Example 354 4-N-[3-(3,5-Dimethyl-1H-pyrazol-1-yl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 351; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.05 (quin, J=6.44 Hz, 2H) 2.20 (s, 3H) 2.21 (d, J=0.51 Hz, 3H) 2.23 (s, 3H) 2.31 (s, 3H) 3.28-3.38 (m, 2H) 4.07 (t, J=6.57 Hz, 2H) 5.00 (br. s., 2H) 5.36 (br. s., 1H) 5.74 (s, 1H) 5.78 (s, 1H) 7.10-7.14 (m, 2H) 7.16 (q, J=4.29 Hz, 1H).

Example 355 6-(2,3-Dimethylphenyl)-4-N-{[1-(pyridin-2-yl)piperidin-3-yl]methyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from [1-(pyridin-2-yl)piperidin-3-yl]methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 389; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.28-1.40 (m, 1H) 1.53-1.67 (m, 1H) 1.73-1.83 (m, 1H) 1.88-2.00 (m, 2H) 2.24 (s, 3H) 2.31 (s, 3H) 3.00 (br. t, J=11.40 Hz, 1H) 3.09 (ddd, J=12.95, 10.04, 3.28 Hz, 1H) 3.17-3.40 (m, 2H) 3.91 (dt, J=12.88, 4.29 Hz, 1H) 4.10 (dd, J=12.88, 3.03 Hz, 1H) 4.99 (br. s., 2H) 5.31 (d, J=2.02 Hz, 1H) 5.83 (s, 1H) 6.57 (ddd, J=7.07, 4.93, 0.88 Hz, 1H) 6.62-6.67 (m, 1H) 7.12-7.19 (m, 3H) 7.45 (ddd, J=8.91, 7.01, 2.02 Hz, 1H) 8.16 (ddd, J=4.93, 2.02, 0.88 Hz, 1H).

Example 356 6-(2,3-Dimethylphenyl)-4-N-[(2-phenyl-2H-1,2,3-triazol-4-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from (2-phenyl-2H-1,2,3-triazol-4-yl)methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 372; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.21 (s, 3H) 2.28 (s, 3H) 4.67 (br d, J=5.31 Hz, 2H) 5.17 (br. s., 2H) 5.58-5.70 (m, 1H) 5.87 (s, 1H) 7.08-7.18 (m, 3H) 7.32-7.38 (m, 1H) 7.45-7.51 (m, 2H) 7.74 (s, 1H) 8.01-8.06 (m, 2H).

Example 357 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-chlorobenzene-1-sulfonamide

Prepared according to general procedure 10 from 4-chlorobenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 446; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.72 (quin, J=6.06 Hz, 2H) 2.21 (s, 3H) 2.30 (s, 3H) 2.90 (d, J=5.05 Hz, 2H) 3.49 (q, J=6.32 Hz, 2H) 3.44-3.52 (m, 2H) 5.33-5.43 (m, 1H) 5.57 (br. s., 2H) 5.78 (s, 1H) 7.05-7.09 (m, 1H) 7.09-7.13 (m, 1H) 7.16-7.20 (m, 1H) 7.41-7.46 (m, 2H) 7.79-7.84 (m, 2H).

Example 358 3-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(4-chlorophenyl)urea

Prepared according to general procedure 11 from 1-chloro-4-isocyanatobenzene and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 425; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 1.85 (t, J=6.69 Hz, 2H) 2.23 (s, 3H) 2.34 (s, 3H) 3.28 (overlap with methanol) 3.50-3.61 (m, 2H) 5.97 (s, 1H) 7.15 (s, 1H) 7.17-7.25 (m, 3H) 7.28-7.37 (m, 3H).

Example 359 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3,5-dimethyl-1,2-oxazole-4-sulfonamide

Prepared according to general procedure 10 from dimethyl-1,2-oxazole-4-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 431; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.79 (br. quin, J=6.0 Hz, 2H) 2.23 (s, 3H) 2.30 (s, 3H) 2.42 (s, 3H) 2.64 (s, 3H) 3.01 (br. q, J=5.90 Hz, 2H) 3.53 (br. q, J=6.00 Hz, 2H) 5.89 (s, 1H) 7.05-7.13 (m, 2H) 7.18-7.21 (m, 1H).

Example 360 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-2-(dimethylamino)acetamide

In a vial 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (10 mg, 0.037 mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (50 mg, 0.32 mmol) were suspended in DCM (1.0 ml), then Et₃N (0.013 ml, 0.092 mmol) was added. The resulting reaction mixture was stirred at r.t. for 1 h. Then MeOH was added and the mixture was stirred 30 min after which the mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 357; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.70-1.78 (m, 2H) 2.28 (s, 3H) 2.31 (s, 3H) 2.35 (s, 6H) 3.06 (s, 2H) 3.34-3.41 (m, 2H) 3.48-3.55 (m, 2H) 5.85 (s, 1H) 7.12-7.16 (m, 2H) 7.17-7.22 (m, 1H).

Example 361 3-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(2,6-dichloropyridin-4-yl)urea

Prepared according to general procedure 11 from 2,6-dichloro-4-isocyanatopyridine and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 460; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.86 (br. quint, J=6.7 Hz, 2H) 2.24 (s, 3H) 2.34 (s, 3H) 3.30-3.34 (m [overlap w MeOH], 2H) 3.55 (br. s., 3H) 5.98 (s, 1H) 7.11-7.24 (m, 2H) 7.27-7.33 (m, 1H) 7.46 (s, 2H).

Example 362 3-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(3,4-difluorophenyl)urea

Prepared according to general procedure 11 from 1,2-difluoro-4-isocyanatobenzene and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 427; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.81-1.89 (m, 2H) 2.24 (s, 3H) 2.34 (s, 3H) 3.25-3.30 (m [overlap w MeOH], 2H) 3.55 (br. s., 2H) 5.98 (s, 1H) 6.94-7.01 (m, 1H) 7.06-7.17 (m, 2H) 7.17-7.23 (m, 1H) 7.27-7.33 (m, 1H) 7.45-7.54 (m, 1H).

Example 363 N-[3-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propoxy)phenyl]acetamide

Prepared according to general procedure 9 from N-[3-(3-aminopropoxy)phenyl]acetamide and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 406; ¹H NMR (400 MHz, DMSO-d₆) δ_(H) ppm 1.96 (t, J=6.32 Hz, 2H) 2.02 (s, 3H) 2.15 (s, 3H) 2.25 (s, 3H) 4.00 (t, J=6.32 Hz, 2H) 5.70 (s, 1H) 5.92 (br. s., 2H) 6.61 (dd, J=8.46, 1.64 Hz, 1H) 6.85-6.99 (m, 1H) 6.99-7.10 (m, 3H) 7.11-7.19 (m, 2H) 7.31 (s, 1H) 9.88 (s, 1H). A signal from one of the CH₂-groups is overlapping with solvent peaks and is not observed by NMR.

Example 364 6-(2,3-Dimethylphenyl)-4-N-[(2-methyl-1H-indol-5-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from (2-methyl-1H-indol-5-yl)methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 358; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.22 (s, 3H) 2.29 (s, 3H) 2.45 (d, J=0.76 Hz, 3H) 4.57 (br. s., 2H) 5.16-5.32 (m, 2H) 5.85 (s, 1H) 6.18-6.21 (m, 1H) 7.05-7.15 (m, 3H) 7.15-7.19 (m, 1H) 7.24-7.28 (m, 1H) 7.47 (s, 1H) 7.97 (br. s., 1H).

Example 365 4-N-[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 337; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.17 (d, J=0.51 Hz, 3H) 2.18 (s, 3H) 2.21 (s, 3H) 2.29 (s, 3H) 2.51-2.63 (m, 1H) 3.68-3.76 (m, 2H) 4.13 (t, J=5.56 Hz, 2H) 5.03 (s, 2H) 5.37-5.47 (m, 1H) 5.71 (s, 1H) 5.77 (s, 1H) 7.07-7.12 (m, 2H) 7.12-7.17 (m, 1H).

Example 366 6-(2,3-Dimethylphenyl)-4-N-[4-(pyrrolidin-1-yl)butyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-(pyrrolidin-1-yl)butan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 340; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.60-1.73 (m, 4H) 1.78-1.86 (m, 4H) 2.24 (s, 3H) 2.31 (s, 3H) 2.49-2.60 (m, 6H) 3.31 (br. s., 2H) 4.79 (s, 2H) 5.46-5.58 (m, 1H) 5.78 (s, 1H) 7.09-7.18 (m, 3H).

Example 367 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-bromobenzamide

4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0 eq) was dissolved in THF (0.50 mL) and NMP (0.050 mL), then Et₃N (1.5 eq) and 3-bromobenzoyl chloride (1.2 eq) were added. The resulting reaction mixture was stirred at rt overnight. The mixture was then concentrated and purified by column chromatography. LCMS [M+H]⁺ 454; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.80-1.89 (m, 2H) 2.23 (s, 3H) 2.30 (s, 3H) 2.37-2.59 (m, 1H) 3.47-3.58 (m, 4H) 5.14 (br. s., 2H) 5.55-5.69 (m, 1H) 5.85 (s, 1H) 7.07-7.13 (m, 2H) 7.17 (dd, J=6.19, 2.91 Hz, 1H) 7.31 (t, J=7.83 Hz, 1H) 7.63 (ddd, J=7.89, 1.96, 1.01 Hz, 1H) 7.75 (dd, J=7.83, 1.01 Hz, 1H) 7.98 (t, J=1.77 Hz, 1H).

Example 368 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzamide

In a vial 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (1.0 eq) was dissolved in NMP (0.050 mL) and THF (0.50 mL), then Et₃N (1.5 eq) and benzoyl chloride (1.0 eq) were added. The resulting reaction mixture was stirred at rt for 1 h. The mixture was then concentrated and purified by column chromatography. LCMS [M+H]⁺ 376; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.86 (t, J=6.06 Hz, 2H) 2.22 (s, 3H) 2.29 (s, 3H) 3.54 (dt, J=12.32, 6.09 Hz, 4H) 5.36-5.54 (m, 1H) 5.89 (s, 1H) 6.14-6.31 (m, 1H) 7.06-7.13 (m, 2H) 7.16-7.20 (m, 1H) 7.40-7.46 (m, 2H) 7.47-7.53 (m, 1H) 7.80-7.85 (m, 2H).

Example 369 1-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-(propan-2-yl)urea

Prepared according to general procedure 11 from 2-isocyanatopropane and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 357; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.12 (d, J=6.57 Hz, 6H) 1.78 (t, J=6.69 Hz, 2H) 2.24 (s, 3H) 2.35 (s, 3H) 3.20 (t, J=6.82 Hz, 2H) 3.45-3.57 (m, 2H) 3.74-3.85 (m, 1H) 5.97 (s, 1H) 7.19 (d, J=14.65 Hz, 2H) 7.30 (s, 1H).

Example 370 Tert-Butyl N-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-carbamate

Prepared according to general procedure 9 from tert-butyl N-(4-aminobutyl)carbamate. LCMS [M+H]⁺ 386; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.45 (s, 9H) 1.54-1.72 (m, 6H) 2.24-2.28 (m, 3H) 2.31 (s, 3H) 3.20 (d, J=6.32 Hz, 3H) 3.33-3.43 (m, 2H) 4.79-4.91 (m, 1H) 5.79-5.83 (m, 1H) 7.14 (s, 2H) 7.16-7.21 (m, 1H).

Example 371 Tert-Butyl N-(5-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}pentyl)-carbamate

Step 1: 4-N-(5-Aminopentyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine was prepared according to general procedure 9 from pentane-1,5-diamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2: 4-N-(5-Aminopentyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (15 mg, 0.028 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.2 mg, 0.033 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.011 mL, 0.085 mmol) was added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified by column chromatography (0→5% in DCM) to afford tert-butyl N-[5-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]pentyl]carbamate. LCMS [M+H]⁺ 400; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.35-1.47 (m, 11H) 1.52 (d, J=7.07 Hz, 2H) 1.58-1.68 (m, 2H) 2.24 (s, 3H) 2.29 (s, 3H) 3.13 (d, J=6.06 Hz, 2H) 3.26-3.37 (m, 2H) 4.58-4.68 (m, 1H) 5.89 (s, 1H) 7.11 (d, J=4.80 Hz, 2H) 7.18 (d, J=4.80 Hz, 1H).

Example 372 Tert-Butyl N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}cyclohexyl)-carbamate

Step 1: 4-N-(2-Aminocyclohexyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine was prepared according to general procedure 9 from cyclohexane-1,2-diamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2: 4-N-(2-Aminocyclohexyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (15 mg, 0.028 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.0 mg, 0.032 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.0050 mL, 0.036 mmol) was added and the resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated and purified by column chromatography (0→5% in DCM) to afford tert-butyl N-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]cyclohexyl]carbamate. LCMS [M+H]⁺ 412; NMR: mixture of cis- and trans-diastereomers: ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.16-1.37 (m, 6H) 1.38-1.42 (m, 18H) 1.53 (br. s., 6H) 1.79 (br. s., 4H) 2.00-2.08 (m, 1H) 2.18-2.23 (m, 1H) 2.25 (d, J=3.79 Hz, 6H) 2.31 (s, 6H) 3.40-3.51 (m, 1H) 3.62-3.75 (m, 1H) 3.83-3.92 (m, 1H) 3.97-4.10 (m, 1H) 4.80-4.93 (m, 1H) 4.97-5.10 (m, 1H) 5.15-5.37 (m, 2H) 5.43-5.67 (m, 2H) 5.75 (s, 1H) 5.83 (s, 1H) 7.09-7.15 (m, 4H) 7.16-7.21 (m, 2H).

Example 373 Tert-Butyl N-(1-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2-methylpropan-2-yl)carbamate

Step 1: 4-N-(2-Amino-2-methyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine was prepared according to general procedure 9 from 2-methylpropane-1,2-diamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine.

Step 2: 4-N-(2-Amino-2-methylpropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (15 mg, 0,029 mmol) and tert-butoxycarbonyl tert-butyl carbonate (7.8 mg, 0.036 mmol) were dissolved in THF (0.50 mL). Then Et₃N (0.0061 mL, 0.044 mmol) was added and the resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated and purified by column chromatography (0→5% in DCM) to afford tert-butyl N-[2-[[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino]-1,1-dimethyl-ethyl]carbamate. LCMS [M+H]⁺ 386; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.34 (s, 6H) 1.43 (s, 9H) 2.26 (s, 3H) 2.31 (s, 3H) 3.53 (d, J=5.81 Hz, 2H) 5.14-5.47 (m, 2H) 5.87 (s, 1H) 7.10-7.16 (m, 2H) 7.18 (d, J=3.28 Hz, 1H).

Example 374 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-cyanobenzene-1-sulfonamide

Prepared according to general procedure 10 from 3-cyanobenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 437; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.70-1.82 (m, 4H) 2.23 (s, 3H) 2.31 (s, 3H) 2.98 (d, J=5.31 Hz, 2H) 3.54 (d, J=5.81 Hz, 2H) 4.71-4.80 (m, 1H) 5.29 (br. s., 2H) 5.76 (s, 1H) 7.07-7.21 (m, 3H) 7.59-7.65 (m, 1H) 7.82 (dt, J=7.64, 1.36 Hz, 1H) 8.14 (dq, J=7.96, 0.97 Hz, 1H) 8.18-8.21 (m, 1H).

Example 375 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from 4-methanesulfonylbenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 490; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 1.73-1.80 (m, 2H) 2.23 (s, 3H) 2.32 (s, 3H) 2.95-3.01 (m, 2H) 3.08 (s, 3H) 3.51-3.58 (m, 2H) 4.69-4.77 (m, 1H) 5.31 (s, 2H) 5.77 (s, 1H) 7.08-7.21 (m, 3H) 8.09 (q, J=8.76 Hz, 4H).

Example 376 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzenesulfonamide

Prepared according to general procedure 10 from benzenesulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 412; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.72 (dt, J=12.06, 5.97 Hz, 2H) 1.76-1.89 (m, 1H) 2.22 (s, 3H) 2.31 (s, 3H) 2.93 (q, J=6.15 Hz, 2H) 3.49 (q, J=6.40 Hz, 2H) 4.70-4.82 (m, 1H) 5.28 (br. s., 2H) 5.72-5.74 (m, 1H) 7.08-7.15 (m, 2H) 7.16-7.20 (m, 1H) 7.45-7.51 (m, 2H) 7.52-7.57 (m, 1H) 7.87-7.92 (m, 2H).

Example 377 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzene-1-sulfonamide

Step 1: tert-butyl N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)carbamate (prepared in example 239) (180 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (2 ml) and stirred at reflux for 1 h. The TFA was evaporated and the crude residue was purified by silica gel chromatography using a gradient of 2-30% MeOH [containing 1 v/v % NH4OH] in DCM which afforded 4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (110 mg, 0.37 mmol). LCMS [M+H]⁺ 300.

Step 2: N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzene-1-sulfonamide was prepared according to general procedure 10 from 3-fluorobenzene-1-sulfonyl chloride and 4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (prepared in step 1). LCMS [M+H]⁺ 458; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 0.92 (s, 6H) 2.16-2.20 (m, 3H) 2.29 (s, 3H) 2.69 (d, J=7.07 Hz, 2H) 3.38 (d, J=6.82 Hz, 2H) 5.91 (s, 1H) 6.53 (s, 1H) 7.04-7.08 (m, 1H) 7.09-7.15 (m, 1H) 7.23-7.30 (m, 1H) 7.38-7.45 (m, 1H) 7.46-7.56 (m, 2H) 7.64 (d, J=7.83 Hz, 1H).

Example 378 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-4-(morpholine-4-sulfonyl)benzene-1-sulfonamide

Step 1: tert-butyl N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)carbamate (prepared in example 239) (180 mg, 0.45 mmol) was dissolved in trifluoroacetic acid (2 ml) and stirred at reflux for 1 h. The TFA was evaporated and the crude residue was purified by silica gel chromatography using a gradient of 2-30% MeOH [containing 1 v/v % NH4OH] in DCM which afforded 4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine (110 mg, 0.37 mmol). LCMS [M+H]⁺ 300.

Step 2: N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-4-(morpholine-4-sulfonyl)benzene-1-sulfonamide was prepared according to general procedure 10 from 4-(morpholine-4-sulfonyl)benzene-1-sulfonyl chloride and 4-N-(3-amino-2,2-dimethyl-propyl)-6-(2,3-dimethyl-phenyl)pyrimidine-2,4-diamine (prepared in step 1 above). LCMS [M+H]⁺ 589; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 0.92 (s, 6H) 2.18 (d, J=0.51 Hz, 3H) 2.28 (s, 3H) 2.71 (d, J=6.82 Hz, 2H) 2.99-3.06 (m, 4H) 3.38 (d, J=6.82 Hz, 2H) 3.70-3.78 (m, 4H) 5.93 (s, 1H) 6.94 (s, 1H) 7.03-7.08 (m, 1H) 7.09-7.15 (m, 1H) 7.25 (d, J=7.58 Hz, 1H) 7.42 (s, 1H) 7.87 (d, J=8.59 Hz, 2H) 8.02 (d, J=8.59 Hz, 2H).

Example 379 6-(2,3-Dimethylphenyl)-4-N-(prop-2-en-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from prop-2-en-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 255; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 2.23 (s, 3H) 2.31 (s, 3H) 3.92 (br. s., 2H) 4.95 (br. s., 3H) 5.18 (dq, J=10.23, 1.47 Hz, 1H) 5.26 (dq, J=17.18, 1.60 Hz, 1H) 5.81 (s, 1H) 5.85-5.96 (m, 1H) 7.10-7.15 (m, 2H) 7.15-7.19 (m, 1H).

Example 380 1-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)imidazolidin-2-one

Prepared according to general procedure 9 from 1-(3-aminopropyl)imidazolidin-2-one and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 341.

Example 381 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-fluorobenzene-1-sulfonamide

Prepared according to general procedure 9 from 3-fluorobenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 430.

Example 382 N-{4-[(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)sulfamoyl]-phenyl}acetamide

Prepared according to general procedure 10 from 4-acetamidobenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 469.

Example 383 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)methanesulfonamide

Prepared according to general procedure 10 from methanesulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 350.

Example 384 N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-3-fluorobenzene-1-sulfonamide

Prepared according to general procedure 10 from 3-fluorobenzene-1-sulfonyl chloride and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 416.

Example 385 N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methoxybenzene-1-sulfonamide

Prepared according to general procedure 10 from 4-methoxybenzene-1-sulfonyl chloride and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 428.

Example 386 6-(2,3-Dimethylphenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from prop-2-yn-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 253.

Example 387 2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetamide

Prepared according to general procedure 9 from 2-aminoacetamide and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 272.

Example 388 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4,5-dichlorothiophene-2-sulfonamide

Prepared according to general procedure 10 from 4,5-dichlorothiophene-2-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 486.

Example 389 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

Prepared according to general procedure 10 from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS [M+H]⁺ 464.

Example 390 2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetonitrile

Prepared according to general procedure 9 from 2-aminoacetonitrile and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 254.

Example 391 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide

Prepared according to general procedure 10 from 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 430; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.69 (s, 2H), 7.33-7.38 (m, 1H), 7.21-7.27 (m, 1H), 7.16-7.20 (m, 1H), 6.00 (s, 1H), 3.71 (s, 3H), 3.58 (s, 2H), 3.06 (s, 2H), 2.45 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H), 1.80-1.90 (m, 2H).

Example 392 N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

Prepared according to general procedure 10 from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS [M+H]⁺ 450.

Example 393 4-N-{2-[(1,3-Benzoxazol-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from 2-chloro-1,3-benzoxazole and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 375.

Example 394 6-(2,3-Dimethylphenyl)-4-N-(4-phenylbutan-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-phenylbutan-2-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 347.

Example 395 4-N-(2,2-Dimethyloxan-4-yl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2,2-dimethyloxan-4-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 327.

Example 396 Ethyl 2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}acetate

Prepared according to general procedure 9 from ethyl 2-aminoacetate and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 301.

Example 397 6-[(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-carbonitrile

Prepared according to general procedure 12 from 6-chloropyridine-3-carbonitrile and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 360; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.32-8.34 (m, 1H), 7.59-7.64 (m, 1H), 7.34-7.38 (m, 1H), 7.22-7.27 (m, 2H), 7.15-7.18 (m, 1H), 6.55-6.59 (m, 1H), 5.97 (s, 1H), 3.72-3.77 (m, 3H), 3.66-3.71 (m, 3H), 2.36 (s, 4H), 2.24 (s, 3H).

Example 398 4-N-{2-[(3-Bromo-1,2,4-thiadiazol-5-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from 3-bromo-5-chloro-1,2,4-thiadiazole and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 420.

Example 399 6-(2,3-Dimethylphenyl)-4-N-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from (5-methyl-4H-1,2,4-triazol-3-yl)methanamine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 310; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.37-7.41 (m, 1H), 7.25-7.30 (m, 1H), 7.20-7.24 (m, 1H), 6.12 (s, 1H), 4.79 (s, 2H), 2.47 (s, 3H), 2.38 (s, 3H), 2.29 (s, 3H).

Example 400 6-(2,3-Dimethylphenyl)-4-N-{2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 2-[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]ethan-1-amine and 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 405.

Example 401 N-(2-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from 4-methanesulfonylbenzene-1-sulfonyl chloride and 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 476; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.10-8.14 (m, 3H), 8.05-8.09 (m, 3H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1H), 7.05-7.08 (m, 1H), 5.73-5.76 (m, 1H), 3.42-3.49 (m, 2H), 3.14 (s, 6H), 2.31 (s, 4H), 2.18 (s, 3H).

Example 402 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from 3-methanesulfonylbenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 490; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 8.43-8.45 (m, 1H), 8.18 (ddd, J=7.8, 1.8, 1.0 Hz, 3H), 8.11 (ddd, J=7.8, 1.8, 1.0 Hz, 3H), 7.67-7.73 (m, 1H), 7.15-7.19 (m, 1H), 7.09-7.13 (m, 1H), 7.08 (d, J=2.0 Hz, 1H), 5.74 (s, 1H), 5.31 (br. s., 2H), 4.82-5.00 (m, 1H), 3.50 (d, J=5.8 Hz, 2H), 3.09 (s, 3H), 2.94 (d, J=4.0 Hz, 2H), 2.29 (s, 3H), 2.20 (s, 3H), 1.71 (t, J=5.8 Hz, 2H).

Example 403 N-(3-{[2-Amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-2-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from 2-methanesulfonylbenzene-1-sulfonyl chloride and 4-N-(3-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine. LCMS [M+H]⁺ 490; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.20-8.33 (m, 3H), 8.10-8.17 (m, 1H), 7.84-7.90 (m, 5H), 7.68-7.80 (m, 3H), 7.16-7.21 (m, 3H), 7.12 (s, 3H), 7.08 (d, J=1.5 Hz, 3H), 5.74 (s, 3H), 3.46 (s, 3H), 3.43 (s, 8H), 3.32-3.36 (m, 3H), 3.07 (t, J=6.7 Hz, 5H), 2.31 (s, 8H), 2.19 (s, 3H), 1.66 (t, J=6.7 Hz, 5H).

Example 404 6-(2,3-Dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 2-(4-methylsulfonylphenyl)ethanamine (1.2 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 397.

Example 405 6-(2,3-dichlorophenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.08 mmol), 2-(4-methylthiazol-5-yl)ethanamine; dihydrobromide (1.2 eq.) and N,N-diisopropylethylamine (4.25 eq.) in n-butanol (0.3 ml) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 380.

Example 406 6-(3-chloro-2-methylphenyl)-4-N-[2-(4-methyl-1,3-thiazol-5-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine (0.14 mmol), 2-(4-methylthiazol-5-yl)ethanamine; dihydrobromide (1.2 eq.) and N,N-diisopropylethylamine (4.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 360.

Example 407 4-N-{[2-(difluoromethyl)pyridin-4-yl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13 mmol), [2-(difluoromethyl)-4-pyridyl]methanamine; hydrochloride (1.2 eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 ml) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 356.

Example 408 6-(2,3-dimethylphenyl)-4-N-[2-(1H-imidazol-4-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13 mmol), 2-(1H-imidazol-4-yl)ethanamine; dihydrochloride (1.2 eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 309.

Example 409 4-N-[3-(1H-1,3-benzodiazol-2-yl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13 mmol), 3-(1H-benzimidazol-2-yl)propan-1-amine (1.2 eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 373.

Example 410 6-(2,3-dimethylphenyl)-4-N-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.14 mmol), (1-methylbenzimidazol-2-yl)methanamine (1.2 eq.) and N,N-diisopropylethylamine (1.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 359.

Example 411 6-(2,3-dimethylphenyl)-4-N-[(2-phenyl-1,3-thiazol-5-yl)methyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.13 mmol), (2-phenylthiazol-5-yl)methanamine hydrochloride (1.2 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 388.

Example 412 6-(3-chloro-2-methylphenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine (0.14 mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanamine hydrochloride (1.2 eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 344.

Example 413 6-(2,3-dichlorophenyl)-4-N-[2-(5-methyl-1H-1,2,4-triazol-3-yl)ethyl]pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.13 mmol), 2-(5-methyl-1H-1,2,4-triazol-3-yl)ethanamine hydrochloride (1.0 eq.) and N,N-diisopropylethylamine (3.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 364.

Example 414 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine (0.14 mmol), 4-(2-aminoethyl)-N,N-dimethyl-benzenesulfonamide (1.0 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 446.

Example 415 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.13 mmol), 4-(2-aminoethyl)-N,N-dimethyl-benzenesulfonamide (1.0 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 466.

Example 416 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol), 4-(2-aminoethyl)-N,N-dimethyl-benzenesulfonamide (1.0 eq.) and N,N-diisopropylethylamine (2.25 eq.) in n-butanol (0.3 mL) was heated in a sealed tube at 110° C. overnight. Methanol was added and the mixture was filtered and purified by preparative HPLC. LCMS [M+H]⁺ 426.

Example 417 4-N-{1-[(4-Chlorophenyl)methyl]cyclopropyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (47 mg, 0.20 mmol), 1-[(4-chlorophenyl)methyl]cyclopropan-1-amine hydrochloride (52 mg, 0.24 mmol) and triethylamine (50 μL, 0.36 mmol) in n-butanol (3 mL) was heated in a sealed tube at 130° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 379.

Example 418 4-N-Cyclopropyl-6-(2,3,4-trichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine (21 mg, 0.050 mmol), cyclopropanamine (25 μL, 0.36 mmol) and triethylamine (25 μL, 0.18 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 329.

Example 419 4-N-[2-(4-Chlorophenyl)ethyl]-6-(2,3,4-trichlorophenyl)pyrimidine-2,4-diamine

A mixture of 4-chloro-6-(2,3,4-trichlorophenyl)pyrimidin-2-amine (21 mg, 0.050 mmol), 2-(4-chlorophenyl)ethan-1-amine (30 μL, 0.24 mmol) and triethylamine (25 μL, 0.18 mmol) in n-butanol (1.5 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 427.

Example 420 6-(2,3-dimethylphenyl)-4-N-(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine (0.15 mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) and triethylamine (101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 232.

Example 421 6-(2,3-dichlorophenyl)-4-N-(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine (0.15 mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) and triethylamine (101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC to afford the product. LCMS [M+H]⁺ 272.

Example 422 6-(2-chloro-3-methylphenyl)-4-N-(²H₃)methylpyrimidine-2,4-diamine

A solution of 4-chloro-6-(2-chloro-3-methylphenyl)pyrimidin-2-amine (0.15 mmol) and d₃-methanamine hydrochloride (70 mg; 1 mmol) and triethylamine (101 mg; 1 mmol) in n-BuOH (2.0 mL) was heated at 95° C. overnight. The reaction mixture was concentrated and purified by preparative HPLC to afford the product. LCMS [M+H]⁺ 252.

Example 423 4-N-[2-(4-Chlorophenyl)ethyl]-6-(1H-pyrrol-2-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 10 from 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine and (1-tert-butoxycarbonylpyrrol-2-yl)boronic acid. The t-butoxycarbonyl group was removed during work-up. LCMS [M+H]⁺ 314; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.29-7.33 (m, 5H), 7.27 (s, 2H), 7.10-7.13 (m, 1H), 6.88-6.92 (m, 1H), 6.33-6.37 (m, 1H), 6.12 (s, 1H), 3.70-3.76 (m, 2H), 2.91-2.96 (m, 2H).

Example 424 N-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-4-methanesulfonylbenzene-1-sulfonamide

Prepared according to general procedure 10 from 4-(methylsulfonyl)-benzenesulfonyl chloride and 4-N-(4-aminobutyl)-6-(2,3-dimethylphenyl)-pyrimidine-2,4-diamine. LCMS [M+H]⁺ 504; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.12-8.17 (m, 2H), 8.06-8.10 (m, 2H), 7.16-7.20 (m, 1H), 7.09-7.14 (m, 1H), 7.05-7.09 (m, 1H), 5.76-5.79 (m, 1H), 3.18 (s, 3H), 2.94-2.99 (m, 2H), 2.31 (s, 3H), 2.19 (s, 3H), 1.50-1.66 (m, 4H).

Example 425 4-(2-{[2-amino-6-(4-fluoro-2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 416; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.07 (dd, J=8.5, 5.9 Hz, 1H), 6.92 (t, J=8.8 Hz, 1H), 5.75 (s, 1H), 3.63 (br. s., 2H), 2.99 (t, J=7.2 Hz, 2H), 2.20-2.23 (m, 6H).

Example 426 4-(2-{[2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 3-cyano-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 409; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.80-7.86 (m, 2H), 7.70 (dd, J=7.8, 1.3 Hz, 1H), 7.53 (d, J=6.8 Hz, 1H), 7.37-7.47 (m, 3H), 5.80 (s, 1H), 3.65 (br. s., 2H), 3.00 (t, J=7.2 Hz, 2H), 2.49 (s, 3H).

Example 427 4-(2-{[2-amino-6-(5-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 5-chloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 418; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.21-7.29 (m, 3H), 5.80 (s, 1H), 3.64 (br. s., 2H), 2.99 (t, J=7.2 Hz, 2H), 2.28 (s, 3H).

Example 428 4-(2-{[2-amino-6-(3,4-dichloro-2-methylphenyl) pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 3,4-dichloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 452; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.88 (d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 7.33-7.36 (m, 1H), 7.15 (s, 1H), 5.73 (s, 1H), 4.87 (s, 2H), 4.81-4.84 (m, 2H), 4.70-4.77 (m, 1H), 3.61-3.69 (m, 2H), 3.01 (s, 2H), 2.41 (s, 3H).

Example 429 6-(3-chloro-2-methylphenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 7 from propargylamine and 4-chloro-6-(3-chloro-2-methyl-phenyl)pyrimidin-2-amine. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.40-7.43 (m, 1H), 7.21 (s, 2H), 5.85-5.88 (m, 1H), 4.13-4.18 (m, 2H), 2.59 (s, 1H), 2.33 (s, 3H).

Example 430 6-(4-fluoro-2,3-dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and 4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 415; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.88 (s, 2H), 7.53-7.58 (m, 2H), 7.06-7.11 (m, 1H), 6.91-6.97 (m, 1H), 5.76 (s, 1H), 3.64-3.72 (m, 2H), 3.11 (s, 3H), 3.02-3.08 (m, 2H), 2.22-2.25 (m, 6H).

Example 431 6-(3,4-dichloro-2-methylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and 3,4-dichloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 451; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.89 (d, J=8.6 Hz, 2H), 7.57 (s, 2H), 7.43-7.46 (m, 1H), 7.17-7.21 (m, 1H), 5.78 (s, 1H), 3.63-3.75 (m, 2H), 3.11 (s, 3H), 3.03-3.08 (m, 2H), 2.39 (s, 3H).

Example 432 4-(2-{[2-amino-6-(4-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 4-chloro-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 418; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.81-7.85 (m, 2H), 7.42-7.46 (m, 2H), 7.27-7.28 (m, 1H), 7.23 (d, J=1.3 Hz, 2H), 5.78 (s, 1H), 3.63 (br. s., 2H), 2.99 (t, J=7.1 Hz, 2H), 2.30 (d, J=0.8 Hz, 3H).

Example 433 4-(2-{[2-amino-6-(2-chloro-4-fluorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 2-chloro-4-fluoro-benzeneboronic acid. LCMS [M+H]⁺ 422.

Example 434 4-(2-{[2-amino-6-(2,3,4-trifluorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 2,3,4-trifluorobenzeneboronic acid. LCMS [M+H]⁺ 424.

Example 435 4-(2-{[2-amino-6-(4-fluoro-3-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 2 from 4-[2-[(2-amino-6-chloro-pyrimidin-4-yl)amino]ethyl]benzenesulfonamide and 4-fluoro-3-methyl-benzeneboronic acid. LCMS [M+H]⁺ 402; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.80-7.85 (m, 2H), 7.67-7.72 (m, 1H), 7.59-7.65 (m, 1H), 7.41-7.46 (m, 2H), 7.07 (dd, J=9.6, 8.6 Hz, 1H), 6.12 (s, 1H), 3.64 (t, J=7.2 Hz, 2H), 2.99 (t, J=7.1 Hz, 2H), 2.31 (d, J=2.0 Hz, 3H).

Example 436 4-N-cyclopropyl-6-(4-fluoro-2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine and 4-fluoro-2,3-dimethyl-benzeneboronic acid. LCMS [M+H]⁺ 273; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.08-7.15 (m, 1H), 6.90-6.98 (m, 1H), 5.90-6.07 (m, 1H), 2.53-2.66 (m, 1H), 2.21-2.26 (m, 6H), 0.78 (dd, J=7.1, 2.0 Hz, 2H), 0.54 (dd, J=3.7, 1.9 Hz, 2H).

Example 437 3-[2-amino-6-(cyclopropylamino)pyrimidin-4-yl]-2-methylbenzonitrile

Prepared according to general procedure 2 from 6-chloro-4-N-cyclopropylpyrimidine-2,4-diamine and 3-cyano-2-methyl-benzeneboronic acid. LCMS [M+H]⁺ 266; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.73-7.77 (m, 1H), 7.58-7.63 (m, 1H), 7.42-7.48 (m, 1H), 5.91-6.17 (m, 1H), 2.59-2.70 (m, 1H), 2.54 (s, 3H), 0.81 (d, J=4.8 Hz, 2H), 0.54-0.59 (m, 2H).

Example 438 6-(2,3-dichlorophenyl)-4-N-(prop-2-yn-1-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dichlorophenyl)pyrimidin-2-amine and propargyl amine. LCMS [M+H]⁺ 293.

Example 439 4-(2-{[2-amino-6-(4-fluoro-2,5-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide

Prepared according to general procedure 9 from 4-chloro-6-(4-fluoro-2,5-dimethyl-phenyl)pyrimidin-2-amine and 2-(4-sulfamoylphenyl)ethylammonium chloride. LCMS [M+H]⁺ 416.

Example 440 4-N-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and 2-(3,5-dimethyl-1H-pyrazol-1-ium-4-yl)ethylammonium dichloride. [M+H]+ 337; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.34 (s, 1H), 7.21-7.26 (m, 1H), 7.18 (dd, J=1.0, 0.5 Hz, 1H), 6.00 (s, 1H), 3.70 (t, J=6.8 Hz, 2H), 2.83 (t, J=6.9 Hz, 2H), 2.39 (s, 6H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 441 4-N-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 12 from 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and 3,6-dichloropyridazine. [M+H]+ 370.

Example 442 2-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-4-carbonitrile

Prepared according to general procedure 12 from 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and 2-chloropyridine-4-carbonitrile. LCMS [M+H]⁺ 360.

Example 443 6-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-sulfonamide

Prepared according to general procedure 12 from 4-N-(2-aminoethyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and 6-chloropyridine-3-sulfonamide. LCMS [M+H]⁺ 414.

Example 444 1-N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzene-1,4-disulfonamide

Prepared according to general procedure 10 from 4-N-(4-aminopropyl)-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine and 4-(aminosulfonyl)benzenesulfonyl chloride. LCMS [M+H]⁺ 491; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.04-8.08 (m, 2H), 7.98-8.02 (m, 2H), 7.28 (d, J=7.1 Hz, 1H), 7.16-7.22 (m, 1H), 7.15 (d, J=1.5 Hz, 1H), 5.91 (s, 1H), 3.48 (d, J=1.5 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.34 (s, 3H), 2.22 (s, 3H), 1.78 (t, J=6.8 Hz, 2H).

Example 445 6-(2,3-dichlorophenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-[2-(4-methylsulfonylphenyl)ethyl]pyrimidine-2,4-diamine and 2,3-dichlorobenzene-boronic acid. LCMS [M+H]⁺ 437; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.90 (d, J=8.6 Hz, 2H), 7.78 (t, J=4.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.49 (dd, J=4.9, 0.6 Hz, 2H), 6.08 (s, 1H), 3.84 (s, 2H), 3.06-3.11 (m, 5H).

Example 446 6-(2,3-dimethylphenyl)-4-N-[1-(1H-pyrazol-1-yl)propan-2-yl]pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)-pyrimidin-2-amine and 1-pyrazol-1-ylpropan-2-amine. LCMS [M+H]⁺ 323; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.71 (d, J=7.8 Hz, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.24 (d, J=7.3 Hz, 1H), 7.12 (t, J=7.6 Hz, 1H), 7.04-7.08 (m, 1H), 6.30 (t, J=2.3 Hz, 1H), 5.85 (s, 1H), 4.65-4.75 (m, 1H), 4.34-4.41 (m, 1H), 4.23 (dd, J=14.1, 6.3 Hz, 1H), 2.29 (s, 3H), 2.18 (s, 3H), 1.16 (d, J=6.8 Hz, 3H).

Example 447 6-(2,3-dimethylphenyl)-4-N-{2-[(3-methoxyphenyl)amino]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and N′-(3-methoxyphenyl)ethane-1,2-diamine. LCMS [M+H]⁺ 364; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.18-7.26 (m, 1H), 7.01-7.07 (m, 1H), 6.96-7.00 (m, 1H), 6.95 (t, J=2.0 Hz, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.76 (dd, J=8.3, 2.0 Hz, 1H), 5.91 (s, 1H), 3.82 (d, J=4.8 Hz, 2H), 3.75 (s, 3H), 3.48 (br. s., 2H), 2.24 (s, 3H), 2.10 (s, 3H).

Example 448 6-(2,3-dimethylphenyl)-4-N-{2-[(3-fluoro-4-methylphenyl)amino]ethyl}pyrimidine-2,4-diamine

Step 1: A vial was charged with 2-fluoro-4-iodo-1-methyl-benzene (240 mg, 1.0 mmol), ethane-1,2-diamine (0.20 mL, 3.0 mmol), CuCl (9.9 mg, 0.10 mmol), and KOH (110 mg, 2.0 mmol). The vial was then flushed with nitrogen and sealed. The mixture was stirred at r.t. for 16 h, thereafter the mixture was extracted with EtOAc. The combined organic phases were dried, concentrated and purified by column chromatography to afford N′-(3-fluoro-4-methyl-phenyl)ethane-1,2-diamine.

Step 2: A mixture of 6-(2,3-dimethylphenyl)-4-chloropyrimidin-2-amine (30 mg, 0.13 mmol), N′-(3-fluoro-4-methyl-phenyl)ethane-1,2-diamine (20 mg, 0.12 mmol), and diisopropylethylamine (0.040 mL, 0.23 mmol) in 2-propanol (0.50 mL) was heated in a sealed tube at 150° C. for 30 min in a microwave reactor. The reaction mixture was then concentrated and purified by preparative HPLC. LCMS [M+H]⁺ 366; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.33-7.37 (m, 1H), 7.21-7.27 (m, 1H), 7.15-7.18 (m, 1H), 6.93-6.99 (m, 1H), 6.38-6.45 (m, 2H), 5.99 (s, 1H), 3.72 (s, 2H), 3.39 (s, 2H), 2.36 (s, 3H), 2.24 (s, 3H), 2.11 (d, J=1.5 Hz, 3H).

Example 449 4-N-{2-[(3,4-dichlorophenyl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and N′-(3,4-dichlorophenyl)ethane-1,2-diamine. LCMS [M+H]⁺ 402; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.33-7.37 (m, 1H), 7.24 (s, 1H), 7.18 (m, 2H), 6.76 (d, J=2.8 Hz, 1H), 6.57 (dd, J=8.8, 2.8 Hz, 1H), 5.97 (s, 3H), 3.69-3.73 (m, 2H), 3.37-3.42 (m, 2H), 2.35 (s, 3H), 2.23 (s, 3H).

Example 450 4-N-{2-[(5-chloropyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and N′-(5-chloro-2-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 369; ¹H NMR (400 MHz, CDCl₃) δ_(H) ppm 7.61-7.69 (m, 2H), 7.30 (d, J=7.6 Hz, 1H), 7.10-7.22 (m, 3H), 6.17 (br. s., 1H), 3.71 (br. s., 4H), 2.33 (s, 3H), 2.24 (s, 3H).

Example 451 4-N-{2-[(5-bromopyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and N′-(5-bromo-2-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 413; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.07 (dd, J=2.3, 0.8 Hz, 1H), 7.86 (dd, J=9.3, 2.3 Hz, 2H), 7.33-7.37 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.15-7.19 (m, 1H), 6.90 (dd, J=9.5, 0.6 Hz, 1H), 6.03 (s, 1H), 3.77-3.82 (m, 2H), 3.64-3.69 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 452 4-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]benzene-1-sulfonamide

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and 4-(2-aminoethylamino)benzenesulfonamide. LCMS [M+H]⁺ 413; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 7.64 (d, J=9.1 Hz, 2H), 7.33-7.37 (m, 1H), 7.24 (s, 1H), 7.15-7.19 (m, 1H), 6.70 (d, J=9.1 Hz, 2H), 6.00 (s, 1H), 3.72-3.77 (m, 2H), 3.45-3.50 (m, 2H), 2.35 (s, 3H), 2.24 (s, 3H).

Example 453 4-N-[2-(4-chlorophenyl)ethyl]-6-(dimethyl-1,2-oxazol-4-yl)pyrimidine-2,4-diamine

Prepared according to general procedure 2 from 6-chloro-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine and (3,5-dimethylisoxazol-4-yl)boronic acid. LCMS [M+H]⁺ 344.

Example 454 6-(2,3-dimethylphenyl)-4-N-{2-[(pyridin-3-yl)amino]ethyl}pyrimidine-2,4-diamine

Prepared according to general procedure 9 from 4-chloro-6-(2,3-dimethylphenyl)pyrimidin-2-amine and N′-(3-pyridyl)ethane-1,2-diamine. LCMS [M+H]⁺ 335; ¹H NMR (400 MHz, CD₃OD) δ_(H) ppm 8.10-8.12 (m, 1H), 7.97-8.00 (m, 1H), 7.72-7.80 (m, 2H), 7.34-7.38 (m, 1H), 7.22-7.27 (m, 1H), 7.19 (dd, J=1.0, 0.5 Hz, 1H), 6.04 (s, 1H), 3.75-3.80 (m, 2H), 3.54 (t, J=6.2 Hz, 2H), 2.36 (s, 3H), 2.25 (s, 3H).

BIOLOGICAL EXAMPLES Biological Example 1 MTH1 Enzymatic Assay and IC50 Value Determination

MTH1 catalyzes the hydrolysis of dGTP to dGMP and PPi. By coupling the reaction to pyrophosphatase added in excess PPi is converted to Pi that can be detected by using the malachite green assay reagent. Briefly, for IC₅₀ value determination the compound to be analyzed is diluted in assay buffer in a 1:3 dilution series generating 12 different compound concentrations giving a final DMSO concentration of 1% in the assay well. MTH1 diluted in assay buffer (100 mM Tris-acetate, 40 mM NaCl, 10 mM magnesium acetate, 1 mM DTT and 0.005% Tween 20) fortified with E. coli pyrophosphatase (0.8 U/ml) is added to a final concentration of 4.8 nM. dGTP diluted in assay buffer is added to a final concentration of 100 μM. The reaction mixture is incubated with shaking for 15 minutes at 22° C. To 100 μl reaction mixture is 25 μl Malachite green assay regent (0.095% Malachite green in 17% H₂SO₄, 1.5% Ammonium molybdate, 0.17% Tween 20) added followed by incubation with shaking for 15 minutes at 22° C. The absorbance of the assay plate is read at 630 nm using an EnVision Multilabel plate reader. The IC₅₀ value is determined by fitting a dose response curve to the data points using nonlinear regression analysis and the equation Y=Bottom+(Top−Bottom)/(1+10^((Log IC₅₀−X)*HillSlope)), where Y is the read absorbance at 630 nm and X is log [compound].

Using this approach the following representative IC₅₀ values were derived. Examples—4, 6, 11, 18, 31, 32, 35, 36, 40, 43, 44, 46, 51, 52, 55, 56, 57, 59, 64, 65, 66, 67, 72, 73, 74, 77, 79, 80, 81, 85, 87, 89, 90, 93, 97, 98, 101, 103, 105, 108, 110, 111, 115, 120, 126, 127, 129, 131, 132, 135, 141, 142, 144, 146, 148, 149, 151, 159, 164, 165, 168, 171, 173, 174, 175, 192, 197, 198, 201, 202, 203, 208, 209, 210, 211, 213, 215, 219, 220, 222, 226, 227, 228, 230, 231, 232, 244, 245, 246, 249, 252, 254, 256, 257, 259, 260, 264, 266, 267, 269, 273, 275, 276, 282, 295, 296, 300, 301, 304, 308, 312, 313, 315, 316, 317, 322, 323, 324, 326, 327, 329, 330, 331, 333, 334, 335, 336, 343, 346, 348, 349, 350, 351, 359, 361, 363, 367, 374, 376, 379, 381, 386, 389, 391, 397, 402, 403, 404, 405, 406, 408, 409, 411, 415, 416, 418, 419, 420, 422, 424, 426, 428, 429, 430, 432, 434, 436, 439, 443, 444, 445, 447, 451, 453, 454 had IC₅₀'s of less than 200 nM

Examples—3, 8, 9, 10, 17, 22, 24, 25, 42, 45, 54, 60, 95, 96, 102, 113, 117, 119, 150, 154, 157, 160, 162, 169, 178, 186, 199, 212, 225, 229, 236, 238, 241, 242, 255, 265, 270, 272, 278, 284, 285, 286, 287, 288, 290, 291, 292, 293, 294, 298, 302, 306, 318, 319, 320, 339, 340, 347, 353, 354, 358, 360, 365, 366, 368, 369, 373, 377, 378, 380, 383, 384, 387, 390, 392, 395, 410, 413, 423, 446 had IC₅₀'s of between 200 nM and 2 μM

Examples—5, 12, 14, 15, 20, 21, 78, 112, 161, 166, 167, 179, 180, 181, 182, 237, 277, 281, 289, 299, 345, 372, 396, 399 had IC₅₀'s of between 2 μM and 10 μM

Biological Example 2 MTH1 siRNA Knock Down and Cell Survival

Cells were cultivated in suitable medium supplemented with 10% FBS and 10 U/ml PeSt. On day 1, cells were seeded at approximately 30% confluency in 6-well plates in complete medium. The day after, the medium was aspired and fresh medium without antibiotics was added. The cells were transfected with All-stars Non-targeting RNA (NT RNA, Qiagen) and MTH1 siRNA (5′-CGACGACAGCUACUGGUUU-3′) and Interferin (Polyplus) according to the manufacturer's protocol. On day 5, cells were either trypsinized, counted and re-seeded for clonogenic outgrowth on 10-cm plates at 500 cells/plate or washed with PBS and scraped in lysis buffer (10 mM Hepes pH 7.1, 50 mM NaCl, 0.3 M sucrose, 0.1 mM EDTA, 0.5% Triton X100, 1 mM DTT and 1× protease inhib, cocktail (Pierce)) and processed for Western blot. Blots were stained with anti-MTH1 antibody (rabbit polyclonal, HPA, KTH, Sweden) and anti-tubulin (mouse monoclonal, Sigma Aldrich). After additional 7-10 days, survival plates were fixed/stained with 4% methylene blue in MeOH and colonies were counted manually. FIG. 1 shows the effect on cell survival following MTH1 siRNA depletion in various human cancer and normal cell lines.

Biological Example 3 Cell Survival Assay

Cells are cultured in DMEM GlutaMAX™ or other suitable cell medium and plated in cell culture dishes (100 mm×20 mm) (500 cells/dish) and incubated in 5% CO₂ at 37° C. After 5 hours of incubation cells are treated with compound at various concentrations and left in the incubator for 7-14 days dependent on cell line. Clonogenic survival is measured by fixating and staining the cells with methylene blue (4 g/L in methanol) and number of colonies are counted and compared to vehicle treated dishes. FIG. 2 shows how an MTH1 inhibitor reduces cell survival in various cancer cell lines, with less effect on normal immortalised cells (VH10 and BJ hTERT).

Biological Example 4 Cell Viability Assay

Cells are seeded into 96 well plates (1500 cells/well) in DMEM GlutaMAX™ or other suitable media dependent on cell line and incubated overnight in 5% CO₂, 37° C. Thereafter cells are treated with compound or vehicle and left in incubator for 3 days until staining with resazurin. Cells are incubated in resazurin (diluted in suitable media) at 37° C. for 2 hours before measuring the fluorescence. 

The invention claimed is:
 1. A compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein: R¹ represents: heteroaryl selected from benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl, and quinolin-5-yl, where the heteroaryl is connected to the pyrimidine of formula I via a carbon atom of the heteroaryl ring, where the heteroaryl is optionally substituted by one or more substituents selected from Y¹, —C₁₋₆alkyl optionally substituted by one or more Y² and heterocycloalkyl optionally substituted by one or more Y³; or aryl represented by

 where E³ and E⁴ each independently represent hydrogen, and E¹ represents —F and E² represent —F, —Cl, —CH₃ or —CF₃, or E¹ represents —Cl and E² represents —F, —Cl, —CH₃ or —CF₃, or E¹ represents —CH₃ and E² represents —F, —Cl, —CH₃—CF₃ or —CN; R² represents hydrogen; R³ represents —C₂₋₆alkyl substituted by one Z¹ each Y¹ independently represents halogen, —CN, —C(O)R^(a), —C(O)N(R^(b))R^(c), —C(O)OR^(d), —N(R^(e))R^(f), —N(R^(g))C(O)R^(h), —N(R^(i))C(O)OR^(j), —N(R^(k))C(O)N(R^(l))R^(m), —NO₂, —N(R^(n))S(O)₂R^(o), —OR^(p), —OC(O)R^(q), —OS(O)₂R^(r), —S(O)_(m)R^(s), —S(O)₂N(R^(t))R^(u), heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; each R^(a), R^(b), R^(c), R^(d), R^(e), R^(g), R^(h), R^(i), R^(k), R^(l), R^(m), R^(n), R^(p), R^(q), R^(s), R^(t) and R^(u) independently represents hydrogen, —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or any two R^(b) and R^(c), R^(e) and R^(f), R^(i) and R^(m) and/or R^(t) and R^(u) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O; each R^(f), R^(j), R^(o) and R^(r) independently represent —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³ or heteroaryl optionally substituted by one or more substituents selected from W³; each Y² independently represents halogen, —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(ml))R^(n1), —N(R^(o1))S(O)₂R^(p1), —OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W²; each Y³ independently represents halogen, —R^(a1), —CN, —C(O)R^(b1), —C(O)N(R^(c1))R^(d1), —C(O)OR^(e1), —N(R^(f1))R^(g1), —N(R^(h1))C(O)R^(i1), —N(R^(j1))C(O)OR^(k1), —N(R^(l1))C(O)N(R^(m1))R^(n1), —N(R^(o1))S(O)₂R^(p1)—OR^(q1), —OC(O)R^(r1), —OS(O)₂R^(s1), —S(O)_(m)R^(t1), —S(O)₂N(R^(u1))R^(v1), heterocycloalkyl optionally substituted by one or more substituents selected from W¹, aryl optionally substituted by one or more substituents selected from W², heteroaryl optionally substituted by one or more substituents selected from W², or ═O; each R^(a1), R^(b1), R^(c1), R^(d1), R^(e1), R^(f1), R^(h1), R^(i1), R^(j1), R^(l1), R^(m1), R^(n1), R^(o1), R^(q1), R^(r1), R^(t1), R^(u1), and R^(v1) independently represents hydrogen, C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; or any two R^(c1) and R^(d1), R^(f1) and R^(g1), R^(m1) and R^(n1) and/or R^(u1) and R^(v1) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 8-membered monocyclic or bicyclic ring, which ring optionally contains one or two heteroatoms and which ring optionally is substituted by one or more substituents selected from W², C₁₋₃alkyl optionally substituted by one or more substituents selected from W¹, and ═O; each R^(g1), R^(k1), R^(p1) and R^(s1) independently represent —C₁₋₆ alkyl optionally substituted by one or more substituents selected from W¹, heterocycloalkyl optionally substituted by one or more substituents selected from W², aryl optionally substituted by one or more substituents selected from W³, or heteroaryl optionally substituted by one or more substituents selected from W³; Z¹ represents —C(O)N(R^(c2))R^(d2), —N(R^(f2))R^(g2), —N(R^(h2))C(O)R^(i2), —N(R^(l2))C(O)N(R^(m2))R^(n2), —N(R^(o2))SO₂R^(p2), —OR^(q2), —S(O)_(m)R^(t2), —S(O)₂N(R^(u2))R^(v2), or aryl represented by

R^(c2), R^(f2), R^(h2), R^(l2),R^(m2), R^(o2), and R^(u2) independently represent hydrogen; R^(d2), R^(g2), R^(i2), R^(n2), R^(p2), R^(q2), R^(t2),and R^(v2) independently represent aryl optionally substituted by one or more substituents selected from W⁶ or heteroaryl optionally substituted by one or more substituents selected from W⁶; each W¹ independently represents halogen, —CN, —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl optionally substituted by one or more substituents selected from G², or ═O; each W², W³, and W⁶ independently represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², heteroaryl (optionally substituted by one or more substituents selected from G², or ═O; W⁷ and W¹¹ each represents hydrogen; each W⁸ and W¹⁰ independently represents hydrogen, halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²; W⁹ represents halogen, —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²; each R^(a3), R^(b3), R^(c3), R^(d3), R^(e3), R^(f3), R^(h3), R^(i3), R^(j3), R^(l3), R^(m3), R^(n3), R^(o3), R^(q3), R^(r3), R^(t3), R^(u3) and R^(v3) independently represents hydrogen or C₁₋₆ alkyl optionally substituted by one or more G³; or any two R^(c3) and R^(d3), R^(f3) and R^(g3), R^(m3) and R^(n3) and/or R^(u3) and R^(v3) are linked together to form, along with the nitrogen atom to which they are attached, a 4- to 6-membered ring, which ring optionally contains one heteroatom and which ring optionally is substituted by one or more G²; each R^(g3), R^(k3), R^(p3), and R^(s3) independently represents C₁₋₆ alkyl optionally substituted by one or more G³; R^(q3x) represents C₂₋₆ alkyl optionally substituted by one or more G³; each G¹ and G² independently represents halogen, —R^(a4), —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O; G³ represents halogen, —CN, —C(O)R^(b4), —C(O)N(R^(c4))R^(d4), —C(O)OR^(e4), —N(R^(f4))R^(g4), —N(R^(h4))C(O)R^(i4), —N(R^(j4))C(O)OR^(k4), —N(R^(l4))C(O)N(R^(m4))R^(n4), —N(R^(o4))S(O)₂R^(p4), —OR^(q4), —OC(O)R^(r4), —OS(O)₂R^(s4), —S(O)_(m)R^(t4), —S(O)₂N(R^(u4))R^(v4), or ═O; each R^(a4), R^(b4), R^(c4), R^(d4), R^(e4), R^(f4), R^(h4), R^(i4), R^(j4), R^(l4), R^(m4), R^(n4), R^(o4), R^(q4), R^(r4), R^(t4), R^(u4) and R^(v4) independently represents hydrogen or —C₁₋₆ alkyl optionally substituted by one or more —F; or any two R^(c4) and R^(d4), R^(f4) and R^(g4), R^(m4) and R^(n4) and/or R^(u4) and R^(v4) are linked together to form, along with the nitrogen atom to which they are attached, a 3- to 6-membered ring, which ring is optionally substituted by one or more —F, —CH₃, —CH₂CH₃, —CHF₂, —CF₃, —CH₂CF₃, or ═O; each R^(g4), R^(k4), R^(p4) and R^(s4) independently represent C₁₋₆ alkyl optionally substituted by one or more —F; each m independently represents 0, 1 or
 2. 2. A compound as claimed in claim 1 wherein: R¹ represents benzofuran-3-yl, benzothiophen-3-yl, dihydrobenzofuran-7-yl, indol-3-yl, indol-4-yl, indol-5-yl, isoquinolin-4-yl, pyridin-3-yl, pyridin-4-yl, pyrrol-2-yl and quinolin-5-y.
 3. A pharmaceutical formulation comprising a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
 4. A method of treatment of a disease selected from the group consisting of soft tissue cancers selected from the group consisting of sarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers/diseases selected from the group consisting of bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma; gastrointestinal cancers/diseases selected from the group consisting of cancers of the esophagus, stomach, pancreas, small bowel, and large bowel; genitourinary tract cancers/diseases selected from the group consisting of cancers of the kidney, bladder and urethra, prostate, and testis; liver cancers/diseases selected from the group consisting of hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers/diseases selected from the group consisting of osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; nervous system cancers/diseases selected from the group consisting of cancer of the skull, meninges, brain, and spinal cord; gynecological cancers/diseases selected from the group consisting of uterus, cervix, ovaries, vulva, and vagina; hematologic cancers; skin cancers/diseases selected from the group consisting of malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids; adrenal glands cancers/diseases, neuroblastoma, neurofibromatosis, head and neck cancers; and breast cancers; wherein the method comprises administering a therapeutically effective amount a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need of such treatment; and wherein the treatment does not comprise prevention or prophylaxis.
 5. A method as claimed in claim 4, wherein the disease is selected from the group consisting of breast cancers, prostate cancers, lung cancers, oesophageal cancers, colon cancers, brain cancers, skin cancers, ovarian cancers, testicular cancers, neurofibromatosis and leukemias.
 6. A combination product comprising: (A) a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof; and (B) one or more other therapeutic agent(s) that is/are useful in the treatment of a disease, wherein each one of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and wherein the treatment does not comprise prevention or prophylaxis; wherein the disease is selected from the group consisting of soft tissue cancers selected from the group consisting of sarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung cancers/diseases selected from the group consisting of bronchogenic carcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, and mesothelioma; gastrointestinal cancers/diseases selected from the group consisting of cancers of the esophagus, stomach, pancreas, small bowel, and large bowel; genitourinary tract cancers/diseases selected from the group consisting of cancers of the kidney, bladder and urethra, prostate, and testis; liver cancers/diseases selected from the group consisting of hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancers/diseases selected from the group consisting of osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumors; nervous system cancers/diseases selected from the group consisting of cancer of the skull, meninges, brain, and spinal cord; gynecological cancers/diseases selected from the group consisting of uterus, cervix, ovaries, vulva, and vagina; hematologic cancers; skin cancers/diseases selected from the group consisting of malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, and keloids; adrenal glands cancers/diseases, neuroblastoma, neurofibromatosis, head and neck cancers; and breast cancers.
 7. A combination product as claimed in claim 6, wherein component (B) is selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors; kinase inhibitors; angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; and cell cycle signaling inhibitors.
 8. A compound as claimed in claim 1 wherein: Z¹ represents

W⁷ and W¹¹ are hydrogen; and (a) W⁸ and W¹⁰ are independently selected from hydrogen, —F, —Cl, —CH₃, —CN, —CF₃; and W⁹ is selected from —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G²; or (b) W⁹ and W¹⁰ are independently selected from hydrogen, —F, —Cl, —CH₃, —CN, —CF₃; and W⁸ is selected from —R^(a3), —CN, —C(O)R^(b3), —C(O)N(R^(c3))R^(d3), —C(O)OR^(e3), —N(R^(f3))R^(g3), —N(R^(h3))C(O)R^(i3), —N(R^(j3))C(O)OR^(k3), —N(R^(l3))C(O)N(R^(m3))R^(n3), —N(R^(o3))S(O)₂R^(p3), —OR^(q3x), —OC(O)R^(r3), —OS(O)₂R^(s3), —S(O)_(m)R^(t3), —S(O)₂N(R^(u3))R^(v3), heterocycloalkyl optionally substituted by one or more substituents selected from G¹, aryl optionally substituted by one or more substituents selected from G², or heteroaryl optionally substituted by one or more substituents selected from G².
 9. A compound as claimed in claim 1, wherein: W⁸ and W¹⁰ each independently represents hydrogen; and W⁹ represents —F, —Cl, —CH₃, cyclopropyl, —CF₃, —CN, —NH₂, —N(CH₃)₂, —N(H)C(O)CH₃, —N(H)C(O)OC(CH₃)₃, —SO₂CH₃, —SO₂NH₂, —S(O)₂N(CH₃)₂, —S(O)₂-4-morpholinyl, 4-methylpiperazin-1-yl, 4-methylpiperidin-1-ylmethyl or 1,2,3-thiadiazol-4-yl.
 10. A compound as claimed in claim 1, selected from: 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine; 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 6-(2,3-dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine; 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 6-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-sulfonamide; 6-(2,3-dichlorophenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine; and 4-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]benzene-1-sulfonamide, or a pharmaceutically acceptable salt thereof.
 11. A compound as claimed in claim 1, selected from: 6-(2,3-dimethylphenyl)-4-N-(2-phenylethyl)pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-[2-(4-methoxyphenyl)ethyl]pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-[2-(4-methylphenyl)ethyl]pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 6-(2, 3-dimethylphenyl)-4-N-(2-phenylpropyl)pyrimidine-2,4-diamine; 6-(2, 3-dimethylphenyl)-4-N-(3-phenylpropyl)pyrimidine-2,4-diamine; 6-(2, 3-dimethylphenyl)-4-N-(2-phenoxyethyl)pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-[2-(phenylamino)ethyl]pyrimidine-2,4-diamine; 6-(2-chloro-3-methylphenyl)-4-N-[2-(4-chlorophenyl)ethyl]pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)ethyl]-6-(1H-indol-4-yl)pyrimidine-2,4-diamine; 6-(3-chloro-2-methylphenyl)-4-N-[(1R)-1-phenylethyl]pyrimidine-2,4-diamine; 6-(3-chloro-2-methylphenyl)-4-N-(2-phenylpropan-2-yl)pyrimidine-2,4-diamine; 4-N-[2-(2-chlorophenoxy)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-[2-(pyridin-3-yloxy)propyl]pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)ethyl]-6-(2,3-dichlorophenyl)pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)ethyl]-6-(quinolin-5-yl)pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)cyclopropyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 3-(2-{[2-amino-6-(2, 3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)phenol; 4-N-{[1-(4-chlorophenyl)cyclopropyl]methyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)phenol; 4-(2-{[2-amino-6-(2, 3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 6-(2,3-dimethylphenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine; 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzonitrile, 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)benzonitrile, 4-N-[2-(3-chlorophenyl)ethyl]-6-(2, 3-dimethylphenyl)pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)propyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-[2-(4-fluorophenyl)ethyl]pyrimidine-2,4-diamine; 4-N-[2-(benzenesulfonyl)ethyl]-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-chlorobenzene-1-sulfonamide; 3-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(4-chlorophenyl)urea; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3,5-dimethyl-1,2-oxazole-4-sulfonamide; 3-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(2,6-dichloropyridin-4-yl)urea; 3-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1-(3,4-difluorophenyl)urea; N-[3-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propoxy)phenyl]acetamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-bromobenzamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-cyanobenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4-methanesulfonylbenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzenesulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-3-fluorobenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}-2,2-dimethylpropyl)-4-(morpholine-4-sulfonyl)benzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-fluorobenzene-1-sulfonamide; N-{4-[(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)sulfamoyl]phenyl}acetamide; N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-3-fluorobenzene-1-sulfonamide; N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methoxybenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-4, 5-dichlorothiophene-2-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-1,2-dimethyl-1H-imidazole-4-sulfonamide; N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide; 4-N-{2-[(1,3-benzoxazol-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-(4-phenylbutan-2-yl)pyrimidine-2,4-diamine; 6-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-carbonitrile, 4-N-{2-[(3-bromo-1,2,4-thiadiazol-5-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; N-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-4-methanesulfonylbenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-3-methanesulfonylbenzene-1-sulfonamide; N-(3-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)-2-methanesulfonylbenzene-1-sulfonamide; 4-(2-{[2-amino-6-(3-chloro-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dichlorophenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 4-(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)-N,N-dimethylbenzene-1-sulfonamide; 4-N-{1-[(4-chlorophenyl)methyl]cyclopropyl-dimethylphenyl)pyrimidine-2,4-diamine; 4-N-[2-(4-chlorophenyl)ethyl]-6-(1H-pyrrol-2-yl)pyrimidine-2,4-diamine; N-(4-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}butyl)-4-methanesulfonylbenzene-1-sulfonamide; 4-(2-[2-amino-6-(3-cyano-2-methylphenyl)pyrimidin-4-yl]amino}ethyl)benzene-1-sulfonamide; 4-N-{2-[(6-chloropyridazin-3-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 2-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-4-carbonitrile, 6-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]pyridine-3-sulfonamide; 1-N-(3-{[2-amino-6-(2, 3-dimethylphenyl)pyrimidin-4-yl]amino}propyl)benzene-1,4-disulfonamide; 6-(2,3-dichlorophenyl)-4-N-[2-(4-methanesulfonylphenyl)ethyl]pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-{2-[(3-methoxyphenyl)amino]ethyl}pyrimidine-2,4-diamine; 6-(2,3-dimethylphenyl)-4-N-{2-[(3-fluoro-4-methylphenyl)amino]ethyl}pyrimidine-2,4-diamine; 4-N-{2-[(3,4-dichlorophenyl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 4-N-{2-[(5-chloropyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 4-N-{2-[(5-bromopyridin-2-yl)amino]ethyl}-6-(2,3-dimethylphenyl)pyrimidine-2,4-diamine; 4-[(2-{[2-amino-6-(2,3-dimethylphenyl)pyrimidin-4-yl]amino}ethyl)amino]benzene-1-sulfonamide; and 6-(2,3-dimethylphenyl)-4-N-{2-[(pyridin-3-yl)amino]ethyl}pyrimidine-2,4-diamine; or a pharmaceutically acceptable salt thereof. 